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1
Homs, Raubert Aïda 1983. "Epigenetic alterations in autism spectrum disorders (ASD)." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/403885.
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The aetiology of autism spectrum disorders (ASD), a group of neurodevelopmental conditions with early onset, characterized by social and communication impairment and restricted interests, is unknown in about a third of the patients. The intense research done over the past decade has revealed a genetic contribution, while the epigenetic contribution barely begins to show. The epigenetic marks can exert an effect in gene expression without altering the underlying genetic sequence. In turn, these marks can be impaired by genetic mutations in their target sequence. Therefore, research in genomic, epigenomic and transcriptomic fields will provide convergent information to unravel the causes of ASD, necessary to establish improved diagnostic protocols and therapeutic strategies, allowing an earlier diagnosis and personalized treatment crucial for a better prognosis. Our data reveal variants associated to the phenotype which shows genetic-epigenetic interplay along with gene expression consequences. It also reveals region epigenetic variants, which follow a polygenic or complex model. Finally, we found ASD genotype-specific epigenetic marks. In the future, the progress in cost-efficiency technologies assessing epigenomics, and the availability of a reference epigenome in various tissues and cell types will provide the background to set a step-forward in establishing the developmental stage, cell types and tissues involved in the epigenetic mechanisms of the disorder.L'etiologia dels trastorns de l'espectre autista (TEA), un grup de malalties del neurodesenvolupament d’aparició primerenca caracteritzades per problemes de comunicació, relació social, i per la presencia d’interessos restringits, és desconeguda per un terç dels individus afectats. La intensa investigació feta durant l'última dècada ha revelat una gran contribució genètica en aquesta malaltia, mentre que de l’epigenètica tot just es comença a evidenciar. Les marques epigenètiques, sense alterar la seqüència genètica subjacent, tenen un efecte en l'expressió dels gens. A la vegada, aquestes marques epigenètiques es poden veure afectades per mutacions genètiques a la seqüència. Així doncs, la recerca en genòmica, epigenòmica i transcriptòmica proporcionarà informació convergent per determinar les causes dels TEA, indispensable per establir millores en els protocols de diagnòstic i en estratègies terapèutiques, facilitant el diagnòstic precoç i el tractament personalitzat, crucial per a un millor pronòstic. Les nostres dades mostren que hi ha alteracions genètiques i epigenètiques associades al fenotip, que interactuen i tenen conseqüències sobre l’expressió gènica. També hem trobat regions amb alteracions epigenètiques, que sembla que contribueixen de manera additiva i seguint un model complex. Finalment, trobem marques epigenètiques específiques de grups de genotips TEA. En el futur, la millora de les tecnologies disponibles per avaluar l’epigenòmica, i la disponibilitat d'un epigenoma de referència en diversos teixits i tipus cel•lulars, serviran com a base per fer un pas cap endavant en l'establiment de l’etapa del desenvolupament, dels tipus cel•lulars i els teixits involucrats en els mecanismes epigenètics del trastorn.
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Modi, Bhavi P. "GENETIC AND EPIGENETIC MECHANISMS OF COMPLEX REPRODUCTIVE DISORDERS." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4574.
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Common, complex disorders are polygenic and multifactorial traits representing interactions between environmental, genetic and epigenetic risk factors. More often than not, contributions of these risk factors have been studied individually and this is especially true for complex reproductive traits where application of genomic technologies has been challenging and slow to progress. This thesis explores the potential of genetic and epigenetic components contributing to a better understanding of the biological pathways underlying disease risk in two specific female complex reproductive traits - polycystic ovary syndrome (PCOS) and preterm premature rupture of membranes (PPROM). The PCOS projects focus on characterization of a gene, DENND1A, whose association to PCOS has been established by Genome Wide Association Studies (GWAS) and is known to contribute to PCOS steroidogenic phenotype. In addition, differential microRNAs expression contributing to DENND1A expression regulation in PCOS theca cells was identified. The studies on PPROM utilize a Whole Exome Sequencing approach to identify rare variants in fetal genes contributing to extracellular matrix composition and synthesis contributing to PPROM risk. The results suggest that fetal contribution to PPROM is polygenic and is driven by a significant genetic burden of potentially damaging rare variants in genes contributing to fetal membrane strength and integrity. Tissue and location specific expression patterns of the Chromosome 21 miRNA cluster (miR-99a, miR-125b, let-7c) in fetal membranes from term pregnancies with spontaneous rupture were investigated. The results suggest that these miRNAs play potential roles in fetal membrane rupture and fetal membrane defects associated with T21.
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Kalushkova, Antonia. "Epigenetic gene regulation in multiple myeloma and mood disorders." Doctoral thesis, Uppsala universitet, Hematologi och immunologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-199494.
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Epigenetics continues to be redefined and new discoveries are likely to revolutionise the field still further. This thesis explores different aspects of how epigenetic regulation of gene expression contributes to human disease. Paper I explores the function of the IKKα kinase in regulating gene expression through the nuclear retinoic acid receptor (RAR). We define a set of genes requiring IKKα for their expression and found recruitment of IKKα to the RAR dependent on structural motifs in its protein sequence. This interplay between the NFκB pathway and nuclear receptor regulated transcription is important to consider when designing therapeutic strategies. Papers II and III focus on the plasma cell malignancy multiple myeloma (MM) and define a gene regulatory circuit defining an underexpressed gene profile in MM dependent on the Polycomb proteins. We provide proof-of-principle that the use of small chemical inhibitors may be operational in reactivating genes silenced by H3K27me3 and that this leads to decreased tumour load and increased survival in the 5T33 in vivo model of MM. We explored the genome-wide distribution of H3K27me3 and H3K4me3, and defined their association with gene expression in freshly-isolated malignant plasma cells from MM patients. Importantly, H3K27me3-marked genes in MM associated with more aggressive stages of the disease and less favourable survival. We present evidence that gene targeting by H3K27me3 is likely to not only involve a small population of tumour cells, but rather represent a common MM profile and further provide a rationale for evaluating epigenetic therapeutics in MM. Paper IV shows that pro-inflammatory gene expression in monocytes of psychiatric patients can be induced in vitro by sodium pump inhibitors, as the steroid hormone ouabain. We suggest that the ouabain-induced gene expression is regulated by an intricate network involving microRNAs, Polycomb and the H3K27me3 demethylase JMJD3. Our data indicates that epigenetic regulators play a role in transmitting cues between intrinsic and/extrinsic stimuli and gene expression in psychiatric illness. This thesis provides novel insights on how seemingly unrelated pathways may converge on transcriptional regulation and evidence that epigenetic modifiers contribute to the pathogenesis of human complex diseases such as multiple myeloma and mood disorders.
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Basil, Paul. "Epigenetic modifications associated with prenatal environmental risk factors for neurodevelopmental psychiatric disorders." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208545.
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Chan, Robin F. "Epigenetic editing to validate findings from methylome-wide association studies of neuropsychiatric disorders." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5003.
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DNA methylation is necessary for learning, memory consolidation and has been implicated in a number of neuropsychiatric disorders. Obtaining high quality and comprehensive data for the three common forms of methylation in brain is challenging for methylome-wide association studies (MWAS). To address this we optimized a panel of enrichment methods for screening the brain methylome. Results show that these enrichment techniques approach the coverage and fidelity of the current gold standard bisulfite based techniques. Our MBD-based method can also be used with low amounts of genomic material from limited human biomaterials. Psychiatric disorders have high prevalence and are often chronic making them a leading contributor to disability. Major depressive disorder (MDD) has a lifetime prevalence of ~15% and high recurrence leading to substantial morbidity and costs to society. The underlying biological processes that contribute to MDD are poorly understood. Noting the importance of DNA methylation in neurobiology, we conducted the largest MWAS in human post-mortem brain uncover novel candidate genes and biomarkers associated with MDD. The top result of this MDD MWAS was within the gene ANKS1B. This gene has been implicated in many past genetic studies of psychiatric disorders and has experimental support as a regulator of neurotransmission. Targeted epigenetic editing technologies allow for precise modification of DNA methylation in living cells. However, an appropriate model system is critical to properly interpreting such experiments. An accelerated protocol for differentiating Ntera2 cells into human neurons was developed for this purpose. Ntera2-derived neurons express key neuronal markers and are well suited to use in epigenetic editing experiments. Concurrently, the generation of the reagents necessary for recapitulating the aberrant methylation at ANKS1B linked to MDD was undertaken. Using a modified CRISPR/Cas9 approach demethylating enzyme was directed to target sites to attempt perform editing of DNA methylation. Results indicate that significant but biologically irrelevant changes to methylation at ANSK1B were achieved. The novelty of the technology employed presented challenges to the success of the current work. However, the field of epigenetic editing is advancing rapidly and will remain an attractive method for functional characterization of future MWAS findings and basic neuroscience research.
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Ziegler, Christiane Verfasser], and Katharina [Gutachter] [Domschke. "Epigenetic Mechanisms in the Pathogenesis and Therapy of Anxiety Disorders / Christiane Ziegler ; Gutachter: Katharina Domschke." Würzburg : Universität Würzburg, 2017. http://d-nb.info/1130587916/34.
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Wells, Layne. "Investigating Neurogenesis as a Veritable Epigenetic Endophenotype for Alzheimer's Disease." Scholarship @ Claremont, 2019. https://scholarship.claremont.edu/scripps_theses/1232.
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Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive amyloid plaque aggregation, neurofibrillary tangles, and cortical tissue death. As the prevalence of AD is projected to climb in coming years, there is a vested interest in identifying endophenotypes by which to improve diagnostics and direct clinical interventions. The risk for complex disorders, such as AD, is influenced by multiple genetic, environmental, and lifestyle factors. Significant strides have been made in identifying genetic variants linked to AD through the genome-wide association study (GWAS). It has been estimated in more recent years, however, that GWAS-identified variants account for limited AD heritability, suggesting the role of non-sequence genetic mechanisms, such as epigenetic moderators. By influencing gene expression, epigenetic markers have been linked to age- associated decline through modulation of chromatin architecture and global genome instability, though such mechanisms are also involved with a number of normal biological processes, including neurogenesis. As the strategies of clinical genetics shift to include a heavier focus on epigenetic contributors, altered adult neurogenesis presents itself as a strong candidate for an endophenotype of AD development. This thesis proposes that, due to neuropathological dysfunction of epigenetic mechanisms in AD, new generations of neurons fail to proliferate, differentiate, and mature correctly, resulting in the larger loss of neurons and cognitive deficits characteristic to neurodegenerative disease. The plasticity of the epigenome and the role of epigenetic factors as mediators of the genome and the environment make such alterations attractive in AD research and implies the potential for therapeutic interventions. The present review submits neurogenesis as a viable target of epigenetic research in AD, highlights shared loci between neurogenesis and AD in the epigenome, and considers the promises and limitations of the neurogenic endophenotype.
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Huang, Hsien-Sung. "Epigenetic Determinants of Altered Gene Expression in Schizophrenia: a Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/365.
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Schizophrenia is a neurodevelopmental disorder affecting 1% of the general population. Dysfunction of the prefrontal cortex (PFC) is associated with the etiology of schizophrenia. Moreover, a substantial deficit of GAD1mRNA in schizophrenic PFC has been reported by different groups. However, the underlying molecular mechanisms are still unclear. Interestingly, epigenetic factors such as histone modifications and DNA methylation could be involved in the pathogenesis of schizophrenia during the maturation of the PFC. In my work, I identified potential epigenetic changes in schizophrenic PFC and developmental changes of epigenetic marks in normal human PFC. Furthermore, mouse and neuronal precursor cell models were used to confirm and investigate the molecular mechanisms of the epigenetic changes in human PFC.
My initial work examined whether chromatin immunoprecipitation can be applied to human postmortem brain. I used micrococcal nuclease (MNase)-digested chromatin instead of cross-linked and sonicated chromatin for further immunoprecipitation with specific anti-methyl histone antibodies. Surprisingly, the integrity of mono-nucleosomes was still maintained at least 30 hrs after death. Moreover, differences of histone methylation at different genomic loci were detectable and were preserved within a wide range of autolysis times and tissue pH values. Interestingly, MNase-treated chromatin is more efficient for subsequent immunoprecipitation than crosslinked and sonicated chromatin.
During the second part of my dissertation work, I profiled histone methylation at GABAergic gene loci during human prefrontal development. Moreover, a microarray analysis was used to screen which histone methyltransferase (HMT) could be involved in histone methylation during human prefrontal development. Mixed-lineage leukemia 1 (MLL1), an HMT for methylation at histone H3 lysine 4 (H3K4), appears to be the best candidate after interpreting microarray results. Indeed, decreased methylation of histone H3 lysine 4 at a subset of GABAergic gene loci occurred in Mll1 mutant mice. Interestingly, clozapine, but not haloperidol, increased levels of trimethyl H3K4 (H3K4me3) and Mll1 occupancy at the GAD1 promoter. I profiled histone methylation and gene expression for GAD1 in schizophrenics and their matched controls. Interestingly, there are deficits of GAD1 mRNA levels and GAD1 H3K4me3 in female schizophrenics. Furthermore, I was also interested in whether the changes of GAD1 chromatin structure could contribute to cortical pathology in schizophrenics with GAD1 SNPs. Remarkably, homozygous risk alleles for schizophrenia at the 5’ end of the GAD1 gene are associated with a deficit of GAD1 mRNA levels together with decreased GAD1 H3K4me3 and increased GAD1H3K27me3 in schizophrenics.
Finally, I shifted focus on whether DNA methylation at the GAD1 promoter could contribute to a deficit of GAD1 mRNA in schizophrenia. However, no reproducible techniques are available for extracting genomic DNA specifically from GABAergic neurons in human brain. Therefore, I used an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of active and silenced gene expression. The methylation frequencies of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined from two chromatin fractions (H3K4me3 and H3K27me3) separately. Consistently, the proximal promoter region of GAD1 is more resistant to methylation in comparison to intron 2 of GAD1 in either open or repressive chromatin fractions. Interestingly, overall higher levels of DNA methylation were seen in repressive chromatin than in open chromatin. Surprisingly, schizophrenic subjects showed a significant decrease of DNA methylation at the GAD1proximal promoter from repressive chromatin.
Taken together, my work has advanced our knowledge of epigenetic mechanisms in human prefrontal development and the potential link to the etiology of schizophrenia. It could eventually provide a new approach for the treatment of schizophrenia, especially in the regulation of methylation at histone H3 lysine 4.
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Nawathe, Aamod. "Fetal epigenetic programming of the IGF axis in pregnancies affected by growth disorders, gestational diabetes and obesity." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/44494.
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Gestational diabetes and maternal obesity are associated with impaired maternal glycaemic control and increased risk of delivering a macrosomic fetus. Macrosomic as well as growth restricted neonates have an increased risk of metabolic syndrome and cardiovascular disease in adult life which may be mediated through an altered intra-uterine environment. The placenta acts as a mediator between the mother and the fetus and handles placental nutrient exchange and transfer. Insulin-like growth factors 1 and 2 (IGF1 and IGF2) are hormones similar to insulin and are known for their growth promoting function in the body. They are also present in the placenta and play an important role in regulating placental and fetal growth. Animal and human studies have shown that IGF1 and IGF2 deletions are associated with growth restriction. The IGFs are bound to their binding proteins called insulin-like growth factor binding proteins (IGFBPs) which modulate their bioavailability and can therefore modulate fetal growth. The IGFs and IGFBPs are associated with glucose regulation but their role in gestational diabetes is unclear. We hypothesized that the placental gene expression of IGF system related genes is altered in pregnancies complicated by fetal growth disorders (pregnancies with small or large fetuses) and in those women who had gestational diabetes mellitus (GDM) or increased body mass index (BMI > 30). Epigenetics is the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence. DNA methylation is an epigenetic mechanism which involves addition of methyl group to a cytosine base in the DNA forming a methylated cytosine-phosphate-guanine (CpG) dinucleotide which is known to silence gene expression. This can potentially alter the expression of IGFs and their binding proteins. We have also hypothesized that a relationship existed between DNA methylation and gene expression of components of the IGF axis in the placenta. The placental IGF1 expression was found to be reduced in women with small for gestational age (SGA) neonates. The expression of IGFBPs was upregulated in SGA neonates and downregulated in large for gestational age (LGA) neonates. The placental IGF1 gene promoter was found to be hypermethylated while the promoters of the binding proteins were hypomethylated in the placentas of SGA neonates. The umbilical cord levels of IGF1 and the binding proteins in SGA and LGA neonates showed a similar trend to the placental gene expression changes. We have also analysed the placental gene expression and umbilical levels of imprinted gene GRB10 which has been investigated in mice studies and is known to cause growth restriction. We found increased placental expression of GRB10 and hypomethylation of its promoter in SGA neonates. The placental expression of IGF1, IGFBP1 and IGFBP2 was found to be decreased in women with GDM on diet and on metformin but not in those on insulin. The IGF1, IGFBP1 and IGFBP2 promoters were noted to be hypermethylated but only in women on diet treatment and not on metformin on insulin. The umbilical levels of IGF1 and IGFBP1 but not IGFBP2, were increased in GDM thus showing an inverse trend to the placental gene expression changes. In conclusion our results suggest that in SGA neonates, changes in CpG methylation contribute to the changes in gene expression of components of the IGF axis and GRB10 in fetal growth disorders. Differential methylation of the IGF1 gene, its binding proteins and GRB10 is likely to play a role in the pathogenesis of SGA neonates. Our results also suggest that GDM is associated with gene expression and epigenetic alterations in the IGF1, IGFBP1 and IGFBP2 genes, which could be part of the wider metabolic complexities associated with GDM.
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Maher, Michael. "An epigenetic approach to fatty acid metabolism in haematological malignancies." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673704.
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The role of fatty acids to overcome stress and contribute to disease progression is becoming increasingly evident in haematological diseases. Further, epigenetic factors play an important role in the aetiology of myelodysplastic syndromes (MDS) and the transformation to secondary acute myeloid leukaemia (sAML). To investigate this in the MDS/sAML cell line, SKK-1, we employed a shRNA knockdown screen to target 912 epigenetic regulators. We then coupled this loss-of-function approach to a fatty acid metabolism-based assay with which we were able to cell-sort the SKK-1 cells based on the fatty acid uptake. Here I describe the methodology of this epigenetics-metabolism approach and our efforts to validate candidate hits from the screen that were predicted to be modulators of fatty acid uptake. Following testing using single gene knockdowns of the top genes from the screen, we were not able to identify epigenetic regulators that significantly alter fatty acid uptake. In parallel, we characterised metabolic and genetic parameters of triple-sorted low (TS LOW) and high (TS HIGH) fatty acid uptake sub- populations. However, during the course of the study, we discovered latent contamination by another myeloid cell line, U-937, in our SKK-1 parental cells and TS LOW and TS HIGH sub-populations. Therefore, we interpreted results from the characterisation study with the knowledge that we had mixed cellular populations. I describe the steps we took to first identify the cell line and then our further characterisation of single cell clones of TS LOW and TS HIGH. Interestingly, we observed distinct cytogenetic profiles between single clones of TS LOW and TS HIGH, namely trisomy 8, which is a highly relevant chromosomal aberration in myeloid malignancies. Overall, this study provides a novel approach to investigate epigenetic and metabolic interactions in blood malignancies. We also find metabolically distinct sub-populations that differ by a disease-relevant karyotype.
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Bastías, Candia Sussy Del Carmen <1979>. "Molecular approach to Neurodegenerative Disorders: Role of Nociceptin/Orphanin FQ - NOP System in Parkinson and Epigenetic Mechanism in Alzheimer's Disease." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4262/.
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With life expectancies increasing around the world, populations are getting age and neurodegenerative diseases have become a global issue. For this reason we have focused our attention on the two most important neurodegenerative diseases: Parkinson’s and Alzheimer’s. Parkinson’s disease is a chronic progressive neurodegenerative movement disorder of multi-factorial origin. Environmental toxins as well as agricultural chemicals have been associated with PD. Has been observed that N/OFQ contributes to both neurotoxicity and symptoms associated with PD and that pronociceptin gene expression is up-regulated in rat SN of 6-OHDA and MPP induced experimental parkinsonism. First, we investigated the role of N/OFQ-NOP system in the pathogenesis of PD in an animal model developed using PQ and/or MB. Then we studied Alzheimer's disease. This disorder is defined as a progressive neurologic disease of the brain leading to the irreversible loss of neurons and the loss of intellectual abilities, including memory and reasoning, which become severe enough to impede social or occupational functioning. Effective biomarker tests could prevent such devastating damage occurring. We utilized the peripheral blood cells of AD discordant monozygotic twin in the search of peripheral markers which could reflect the pathology within the brain, and also support the hypothesis that PBMC might be a useful model of epigenetic gene regulation in the brain. We investigated the mRNA levels in several genes involve in AD pathogenesis, as well DNA methylation by MSP Real-Time PCR. Finally by Western Blotting we assess the immunoreactivity levels for histone modifications. Our results support the idea that epigenetic changes assessed in PBMCs can also be useful in neurodegenerative disorders, like AD and PD, enabling identification of new biomarkers in order to develop early diagnostic programs.
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Parira, Tiyash. "Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-derived Dendritic Cells." FIU Digital Commons, 2018. https://digitalcommons.fiu.edu/etd/3890.
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The effects of alcohol abuse are multi-dimensional since alcohol is widely known to affect both the innate and adaptive immune systems. Recently, epigenetics has come into focus and has been implicated in many diseases as well as substance abuse disorders. Therefore, research efforts of understanding the epigenetic mechanisms underlying substance abuse effects including alcohol abuse have become more predominant.
In our laboratory, we have studied different epigenetic changes induced by alcohol exposure including regulation of histone deacetylases (HDACs), histone quantity, and histone modifications such as acetylation and deacetylation. We have observed differential effects of acute and chronic alcohol exposure in human monocyte-derived dendritic cells (MDDCs) wherein our laboratory previously found that HDACs were modulated in MDDCs treated acutely with alcohol in vitro, and in MDDCs from alcohol users. Our previous work has also demonstrated that alcohol consumption affects the dendritic cell function by modulating inflammatory markers and cannabinoid receptors such as CB2 and GPR55 through epigenetic modifications. For instance, chronic alcohol exposure upregulates histone (H) 4 acetylation at lysine 12 (H4k12ac) and acute alcohol effects on histone acetylation are associated with an increase in GPR55 expression.
The hypothesis of the study is that chronic alcohol modulates human MDDC function through epigenetic mechanisms. Therefore, the primary objective of this research project is to elucidate novel pathways involving histone post-translational modifications due to chronic alcohol exposure in human dendritic cells.
For this study, monocytes isolated from commercially available human buffy coats were differentiated into MDDCs, which were treated with chronic alcohol levels of 0.1 % (100mg/dL) and 0.2 % (200mg/dL) for 5 days in the presence or absence of the histone acetyltransferase inhibitor NU9056 (50nM) or the GPR55 antagonist CID16020046 (5µM). Results showed that chronic alcohol levels upregulated H4K12ac in MDDCs and this was associated with a concomitant increase in GPR55 gene and protein expression. Further, NU9056 and CID16020046 were able to reduce alcohol-induced inflammatory chemokine MCP-2 and reactive oxygen species production indicating that H4K12ac may be an inflammation and oxidative stress regulator. Additionally, NU9056 and CID16020046 could potentially reduce alcohol-induced inflammation and serve as potential therapeutic targets for alcohol use disorders.
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Miemczyk, Stefan. "Towards the identification of environmental exposures and epigenetic marks related to the etiology of Autism." Thesis, Linköpings universitet, Biologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-138946.
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Autism is a complex disorder with possible genetic, epigenetic and environmental components. As the etiology remains uncertain and an increase in incidence is suspected, the involvement of possible environmental risk factors has gained increasing attention. With this thesis, I aim to provide tools for assessing such risk factors. Firstly, I aim to construct a questionnaire for the analysis of an environmental component in the etiology of autism. Secondly, I aim to assess the importance of prenatal exposure to metals in certain diseases and thirdly I aim to construct a methodology enabling the analysis of the mitochondrial epigenome, which is especially interesting in relation to autism as mitochondrial diseases occur more frequently in an autistic population than in the general population. For the creation of the questionnaire the scientific literature was reviewed. The resulting questionnaire contains general, prenatal, neonatal and paternal risk factors. The metal analysis was conducted on the cord blood of patients who later developed autism, antinuclear antibodies positive rheumatoid arthritis or diabetes, which were then compared to healthy control subjects. My findings propose a link between elevated levels of cord blood cadmium or aluminum and rheumatic arthritis. In addition, elevated aluminum levels might be associated with autism. In regards to the analysis of the mitochondrial epigenome, to my knowledge, no standard protocol exists with frozen human whole blood as a source. In this thesis, I succeeded in creating the basis for such a protocol, however still needing several small modifications for an increased overall yield.
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Mundorf, Annakarina [Verfasser], Nadja [Gutachter] Freund, and Stefan [Gutachter] Herlitze. "Epigenetic influences during development and their neurobiological consequences in psychiatric disorders / Annakarina Mundorf ; Gutachter: Nadja Freund, Stefan Herlitze ; Fakultät für Biologie und Biotechnologie." Bochum : Ruhr-Universität Bochum, 2020. http://d-nb.info/1221370227/34.
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Boulle, Fabien. "Les régulations épigénétiques au niveau de la signalisation BDNF-TRKB dans la physiopathologie et traitement des troubles anxio-dépressifs." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05P617/document.
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Les troubles de l’humeur font partie des problèmes de santé majeurs dans le monde, du fait de leur forte incidence et récurrence dans la population générale, de la nuisance pour la qualité de vie des patients ainsi que la répercussion majeure sur les systèmes de santé. A ce jour, l’étiologie ainsi que les mécanismes biologiques sous-jacents les troubles de l’humeur sous encore très mal connus. Un nombre grandissant de preuves suggère qu’une interaction complexe entre les gènes et l’environnement serait a l’origine de la mise en place et évolution des épisodes dépressifs majeurs – un des troubles de l’humeur les plus répandus. Par conséquent, des régulations épigénétiques complexes, qui consistent en des mécanismes clefs par lesquels l’environnement induit des changements persistant sur l’expression des gènes (sans modifier le code génétique), joueraient un rôle prépondérant dans la pathophysiologie de la dépression. De manière plus spécifique, la répression épigénétique du gène codant pour le brain-derived neurotrophic factor (BDNF) – un facteur de croissance impliqué dans la plasticité neuronale et développement du système nerveux central – serait un mécanisme clef dans la mise en place de la dépression et autres troubles de l’humeur. Dans ce contexte, les travaux de recherche présentés dans cette thèse visent à explorer le rôle des régulations épigénétiques au niveau de la signalisation BDNF/TrkB dans la physiopathologie et traitement des troubles de l’humeur. Les résultats montrent que les régulations épigénétiques au niveau de la signalisation BDNF/TrkB sont fortement impliquées dans la mise en place et maintenance de la plasticité neuronale. De plus, les variations environnementales, particulièrement au cours du développement, sont capables d’induire une reprogrammation épigénétique stable et persistante au niveau du complexe BDNF/TrkB ainsi qu’une altération de la neuroplasticité, conduisant à une augmentation de la vulnérabilité au stress et troubles de l’humeur. De manière intéressante, la signalisation du récepteur TrkB est nécessaire pour les effets neurobiologiques et comportementaux des antidépresseurs. De ce fait, une approche pharmocologique ciblée sur le complexe BDNF/TrkB et ses régulations épigénétiques sous-jacentes apparaît comme stratégie thérapeutique prometteuse pour le traitement des troubles de l’humeur tel que la dépressionMood disorders are among the major health problems worldwide due to the high prevalence and recurrence in the general population, and the significant burden for individual life quality and the repercussion on healthcare systems and society. Up to date, the etiology and biological mechanisms underlying mood disorders are still poorly understood. Mounting evidences suggest that a complex interaction between genes and environment might account in the development and course of major depression i.e. one of the most prevalent affective disorders. Accordingly, complex epigenetic regulations - consisting of key mechanisms by which environmental factors induce enduring changes in gene expression without altering the DNA code - have been suspected to plays a pivotal role in the pathophysiology of depression. More specifically, epigenetic repression of the gene encoding for brain-derived neurotrophic factor (BDNF) - a small-secreted growth factor implicated in brain development and neuronal plasticity - may have a preponderant role in the onset of depression and other mood disorders. In this context, the research presented in this thesis aimed at exploring the role of BDNF signaling and its downstream epigenetic regulations in the pathophysiology and treatment of mood disorders. Our findings indicate that epigenetic regulation at BDNF/TrkB signaling is critically important in the establishment and maintenance of neuronal plasticity. Moreover, environmental variations, especially when occurring in development, are able to induce stable and enduring epigenetic reprogramming involving aberrant BDNF/TrkB signaling and impaired neuroplasticity, thereby increasing vulnerability to stress and mood disorders. Interestingly, antidepressants require TrkB to exert some of their neurochemical and behavioral effects. Hence, targeting the BDNF receptor TrkB to restore a normal epigenetic regulation and neuronal functioning appears to be a promising strategy for the treatment of mood disorders
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Rovira, Lorente Paula. "Genetic and epigenetic signatures of attention-deficit/hyperactivity disorder." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/672728.
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Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental, complex and highly heritable disorder characterised by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that impair the daily functioning of patients. These symptoms typically initiate in childhood and persist over time in around two thirds of the diagnosed children. There is evidence that both common and rare genetic variants contribute to the risk for the disorder, with heritability estimates around 76% that seem to remain stable across the lifespan. However, the genetic variation associated with ADHD to date only explain a modest proportion of the phenotypic variance. In this context and taking into account that environmental factors also play a role into the disorder’s susceptibility, it has been proposed that epigenetic marks such as DNA methylation (DNAm) could be contributing as plausible mechanisms by which environmental influences lead to functional and/or structural brain alterations found in ADHD.
Given this background and bearing in mind that the genetic and epigenetic investigations conducted on ADHD have been mainly focused on its childhood presentation, the objectives of the present doctoral thesis have been to explore the contribution of common genetic variants to the risk for ADHD across the lifespan and to examine whether there are DNAm patterns specifically associated with ADHD in adults.
Firstly, to investigate the genetic basis of ADHD through a lifespan perspective, we have conducted the largest meta-analysis of genome-wide association studies (GWAS-MA) on persistent ADHD in adults to date, a GWAS-MA on ADHD in childhood, and a GWAS- MA on ADHD across the lifespan using data from children and adults in a total sample of 17,149 cases and 32,411 controls. Through this approach, we have identified nine new independent loci associated with ADHD across the lifespan and we have shown that the proportion of common genetic variation contributing to the disorder seems to be stable over time. Moreover, our results have revealed a high genetic overlap between ADHD in childhood and persistent ADHD in adults, driven by the whole group of children, and similar patterns of genetic correlation between ADHD and other ADHD-related phenotypes and different traits and disorders across the lifespan.
Secondly, by conducting the largest epigenome-wide association study (EWAS) of ADHD in adults to date, comprising 103 clinical samples of adults with ADHD and 100
controls, we have identified DNAm patterns associated with ADHD in adults. Our results have shown that these patterns are not driven by the individuals’ smoking status or polygenic risk burden for ADHD, neither by exposure to stressful life events in the group of cases. Moreover, the localization of these DNAm patterns in or near genes previously involved in cancer, and the enrichment found for epigenetic signatures of smoking behaviour and maternal smoking among our findings, have reinforced that smoking behaviour is a key factor to account for in this type of analyses. In addition, our enrichment analyses results have supported that genome-wide DNAm is developmental- stage specific and point to an overlap between genetic and epigenetic signatures in ADHD that needs to be further studied in larger samples.
In conclusion, the results of the present doctoral thesis provide new insights into the genetic basis of ADHD across the lifespan, support the hypothesis of the neurodevelopmental origin of persistent ADHD in adults, and shed light on the epigenetic signatures characterising ADHD in adults.El trastorn per dèficit d'atenció i hiperactivitat (TDAH) és un trastorn del neurodesenvolupament, complex i altament heretable caracteritzat per símptomes d’inatenció, impulsivitat i hiperactivitat inapropiats per l’edat que deterioren el funcionament diari dels pacients. Aquests símptomes normalment s’inicien a la infància i persisteixen en el temps en aproximadament dos terços dels nens diagnosticats. Hi ha evidències que recolzen que tant variants genètiques comunes com rares contribueixen al risc del trastorn, amb una heretabilitat estimada al voltant del 76% que sembla mantenir- se estable al llarg de la vida. Tanmateix, la variació genètica associada al TDAH fins ara només explica una modesta proporció de la variància fenotípica. En aquest context, i considerant que els factors ambientals també tenen un paper en la susceptibilitat al trastorn, s’ha proposat que les marques epigenètiques com la metilació de l’ADN (ADNm) podrien contribuir com a mecanismes mitjançant els quals les influències ambientals condueixen a alteracions funcionals i/o estructurals del cervell en el TDAH. Tenint en compte aquest context i donat que les investigacions genètiques i epigenètiques realitzades sobre el TDAH s’han centrat principalment en la seva presentació infantil, els objectius de la present tesi doctoral han sigut explorar la contribució de les variants genètiques comunes al risc de TDAH al llarg de la vida i examinar si hi ha patrons d’ADNm associats específicament amb el TDAH en adults. En primer lloc, per investigar les bases genètiques del TDAH al llarg de la vida, hem realitzat la meta-anàlisi més gran d’estudis d’associació de genoma complet (GWAS- MA) en TDAH persistent en adults fins al moment, una GWAS-MA en TDAH a la infància i una GWAS-MA en TDAH al llarg de la vida amb dades de nens i adults en una mostra total de 17,149 casos i 32,411 controls. Mitjançant aquesta aproximació, hem identificat nou nous loci independents associats amb el TDAH al llarg de la vida i hem mostrat que la proporció de variants genètiques comunes que contribueix al trastorn sembla ser estable al llarg del temps. A més, els nostres resultats han revelat un elevat solapament genètic entre el TDAH en la infància i el TDAH persistent en adults, degut a tot el grup de nens, i patrons de correlació genètica similars entre el TDAH i altres fenotips relacionats amb el TDAH i diferents trets i trastorns al llarg de la vida. En segon lloc, realitzant l’estudi d’associació d’epigenoma complet (EWAS) més gran realitzat en el TDAH en adults fins al moment, que comprèn 103 mostres clíniques d’adults amb TDAH i 100 controls, hem identificat patrons d’ADNm associats al TDAH en adults. Els nostres resultats han mostrat que aquests patrons no són deguts al tabaquisme, a la càrrega de risc poligènic per al TDAH, ni a l’exposició a situacions vitals estressants en el grup de casos. A més, la localització d’aquests patrons d’ADNm en gens prèviament implicats en el càncer i l’enriquiment que hem trobat en els nostres resultats per a patrons d’ADNm que caracteritzen el tabaquisme i el tabaquisme matern durant l’embaràs, han reforçat que el tabaquisme és un factor clau a tenir en compte en aquest tipus d’anàlisis. Addicionalment, els resultats de les nostres anàlisis d’enriquiment han recolzat que els patrons d’ADNm en tot el genoma són específics del període de desenvolupament de l’individu i assenyalen un solapament entre marques genètiques i epigenètiques en el TDAH que cal estudiar en més profunditat en mostres més grans. En conclusió, els resultats de la present tesi doctoral proporcionen nou coneixement sobre la base genètica del TDAH al llarg de la vida, donen suport a la hipòtesi de l’origen del TDAH persistent en adults en el neurodesenvolupament i posen de manifest marques epigenètiques que caracteritzen el TDAH en adults.
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Shivalikanjli, Anu. "Genetics and epigenetics of attention-deficit/hyperactivity disorder and comorbid conditions." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673465.
Full textAbstract:
The broad objectives of this work are the identification of genes that contribute to the susceptibility to attention-deficit/hyperactivity disorder (ADHD) and cocaine dependence, two disorders that co-occur in patients. In this Thesis, we describe (i) the contribution to ADHD of allele-specific methylation (ASM), an epigenetic mechanism that involves single single- nucleotide polymorphisms (SNPs) correlating with differential levels of DNA methylation at CpG sites, (ii) the role of microRNA (miRNA) genes in ADHD, and (iii) a genome-wide association meta-analysis of cocaine dependence. We also explore the common genetic basis that explains the comorbidity between these disorders.
The main results from the three studies include:
(i) Common genetic risk variants for ADHD identified in a previous genome-wide association study (GWAS) that included 20,000 cases and 35,000 controls are enriched in SNPs that correlate with levels of DNA methylation. Eight ASM SNPs were found significantly associated with ADHD and correlated with differential methylation at six CpG sites in cis in different brain areas. These six CpG sites are located at possible promoter regions of six genes expressed in brain: ARTN, C2orf82, NEUROD6, PIDD1, RPLP2 and GAL. Based on the bioinformatic functional analyses of these genes, our study highlights the candidacy of ARTN, C2orf82 and PIDD1 genes as potential contributors to ADHD susceptibility.
(ii) We conducted a case-control association study to investigate the contribution to ADHD of common genetic variation in 1,761 autosomal miRNAs using pre-existing GWAS data from
20,000 cases and 35,000 controls. We identified significant associations of SNPs with ADHD that highlight 12 miRNA genes, all located within protein-coding genes. The associated variants are located in the putative regulatory regions of the miRNA genes or in the promoter region of the host protein-coding gene. We inspected the target genes, brain expression, homologs for the miRNAs and we propose miR-7-1 and miR-3666 as promising candidates since both are brain expressed, have validated brain-expressed targets, and homologs in model species. Pathway analysis of ADHD-associated miRNAs revealed miRNA-mediated regulation of serotonin receptor genes, well-known contributors to neurological functions and diseases.
(iii) We performed the largest cocaine dependence GWAS meta-analysis in individuals of European ancestry, including 2,100 cases and 4,300 controls. Although SNP-based analysis revealed no genome-wide significant associations with cocaine dependence, probably due to limited sample size, gene-based analysis identified the HIST1H2BD gene, previously associated with schizophrenia. The estimated SNP-based heritability of cocaine dependence was estimated as 30%. A significant genetic correlation was found between cocaine dependence and ADHD, schizophrenia, major depressive disorder and risk-taking behaviour, suggesting a shared genetic basis across pathologies and traits. Polygenic risk score (PRS) analysis shows that all the comorbid features analysed (ADHD, schizophrenia, major depressive disorder, aggressiveness, antisocial personality or risk-taking behaviour) can predict cocaine dependence.
Overall, we identified common genetic and epigenetic risk factors that underlie the susceptibility to ADHD and to cocaine dependence. The results reinforce the idea that epigenetic mechanisms dictate the differential expression of genes that may be causal to ADHD. Cocaine dependence, which has been widely believed to occur under environmental and epigenetic influences, is also in part genetically determined. Finally, ADHD and cocaine dependence are comorbid disorders, and the observed genetic correlation between these conditions can reflect biological pleiotropy.Aquest treball té com a objectiu principal la identificació de gens que contribueixen a la susceptibilitat al trastorn per dèficit d’atenció amb hiperactivitat (TDAH) i a la dependència de cocaïna, dos trastorns que es presenten amb freqüència conjuntament en pacients. En aquesta Tesi es descriu (i) la contribució al TDAH de la metilació específica de l’al·lel (ASM), un mecanisme epigenètic pel qual variants polimòrfiques presenten correlació amb nivells diferencials de metilació de l’ADN en llocs CpG, (ii) el paper dels gens de microRNAs (miRNAs) en el TDAH, i (iii) una meta-anàlisi d’estudis d’associació a escala genòmica de la dependència de cocaïna. També explorem la base genètica comuna que explica la comorbiditat entre aquests dos trastorns. Els principals resultats dels tres estudis són: (i) Les variants genètiques comunes de risc al TDAH identificades en un estudi previ d’associació a escala genòmica (GWAS) amb 20.000 casos i 35.000 controls estan enriquides en variants de canvi d’un sol nucleòtid (SNPs) que tenen influència sobre la metilació de l’ADN. Vuit SNPs de tipus ASM estan associats significativament amb el TDAH i presenten correlació amb la metilació diferencial de sis dinucleòtids CpG en cis en diferents àrees cerebrals. Aquests sis llocs CpG estan en possibles regions promotores de sis gens que s’expressen al cervell: ARTN, C2orf82, NEUROD6, PIDD1, RPLP2 i GAL. En base a anàlisis bioinformàtiques d’aquests gens a nivell funcional, el nostre estudi prioritza els gens ARTN, C2orf82 i PIDD1 com a possibles contribuents a la susceptibilitat al TDAH. (ii) Hem dut a terme un estudi d'associació cas-control per investigar la contribució al TDAH de la variació genètica comuna en 1.761 miRNA autosòmic s utilitzant dades GWAS preexistents de 20.000 casos i 35.000 controls. Hem identificat associacions significatives de SNPs amb el TDAH que assenyalen 12 gens de miRNAs, tots situats dins de gens que codifiquen proteïnes. Les variants associades estan situades en suposades regions reguladores dels gens de miRNA o a la regió promotora del gen hoste. Hem inspeccionat els gens diana dels miRNAs, la seva expressió en cervell i els gens homòlegs en altres espècies, i proposem els gens miR-7-1 i miR-3666 com a candidats prometedors, ja que tots dos són s’expressen al sistema nerviós central, tenen dianes validades que s’expressen també en cervell i tenen homòlegs en espècies model. L’anàlisi de vies a partir dels miRNAs associats al TDAH ha assenyalat gens de receptors de serotonina regulats pels nostres miRNAs, la relació dels quals amb funcions i malalties neurològiques és ben coneguda. (iii) Hem realitzat la metaanàlisi més gran fins ara de dades GWAS de dependència de cocaïna en individus d'ascendència europea, amb 2.100 casos i 4.300 controls. Tot i que l’anàlisi basada en SNPs no ha revelat cap associació significativa amb la dependència de cocaïna, probablement a causa de la mida mostral limitada, l’anàlisi basada en gens ha permès identificar el gen HIST1H2BD, anteriorment associat a l’esquizofrènia. Hem calculat també l'heretabilitat basada en SNPs de la dependència de cocaïna, que seria d’un 30%. Hem detectat una correlació genètica significativa entre la dependència de cocaïna i el TDAH, l’esquizofrènia, el trastorn depressiu major i els comportaments de risc, tot suggerint que hi ha una base genètica compartida entre patologies i trets. L’anàlisi de la puntuació de risc poligènic (PRS) mostra que totes les característiques comòrbides analitzades (TDAH, esquizofrènia, trastorn depressiu major, agressivitat, personalitat antisocial o comportament s de risc) prediuen la dependència de la cocaïna. En resum, hem identificat factors de risc genètics i epigenètics freqüents a la població que contribueixen a la susceptibilitat al TDAH i a la dependència de cocaïna. Els resultats reforcen la idea que els mecanismes epigenètics estan relacionats amb l'expressió diferencial de gens que poden contribuir al TDAH. La dependència de cocaïna, que fins ara s’havia relacionat amb factors de risc ambientals i epigenètics, també estaria determinada, en part, per factors genètics. Finalment, el TDAH i la dependència de la cocaïna són trastorns comòrbids i la correlació genètica observada entre aquestes afeccions pot reflectir pleiotropia biològica.
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Azoulay, Nelson. "Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder: examining child vs. adult trauma." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104876.
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PTSD is a devastating disorder that affects 7-12% of individuals who experience a traumatic event in their lives. Individuals suffering from the disorder show a dysfunctional HPA axis with decreased basal cortisol release and increased glucocorticoid receptor sensitivity. Recently, epigenetic studies have shown associations between trauma and the subsequent effects on the HPA axis in abused participants who committed suicide. Importantly, findings also showed child trauma as being a significant factor in DNA methylation levels in promoter region 1F in the hippocampus. This thesis shows the possible role of epigenetic programming of glucocorticoid receptors in PTSD while examining the effects of different timing of trauma. Methods included the measurements of salivary basal cortisol levels, the expression of glucocorticoid receptors in whole blood and the DNA methylation levels in two promoter regions of the glucocorticoid receptors by sequenome epityper. Results showed that individuals suffering from PTSD have decreased salivary cortisol release in the morning, increased glucocorticoid receptors and increased total methylation levels in promoter region 1C in whole blood. Additionally, adulthood trauma seemed to be of greater importance with regards to HPA axis activity while childhood trauma showed to be more significant with regards to epigenetics. These results indicate that 1) individuals suffering from a lifetime PTSD have a dampened HPA axis activity, 2) epigenetics play a different role in PTSD compared to abused individuals who have committed suicide and 3) timing of trauma has a significant effect on both the HPA axis activity and the epigenetic modifications.Le TSPT est un syndrome dévastateur qui touche entre 7 et 12% de gens qui vivent un événement traumatique. Les personnes qui souffrent du syndrome ont un axe HPA dysfonctionnel avec moins de cortisol salivaire et une augmentation de sensitivité des récepteurs glucocorticoïdes. Il y a récemment eu des études épigénétiques qui ont montré une association entre les traumas et les effets sur l'axe HPA chez des patients abusés qui ont commis un suicide. De plus, les résultats indiquent qu'un trauma durant l'enfance est un facteur significatif pour la méthylation d'ADN dans la région promoteur 1F de l'hippocampe. Cette thèse présente le possible rôle modulateur de l'épigénétique des récepteurs glucocorticoïdes chez les personnes touchées du TSPT tout en examinant les effets du temps du trauma. Les résultats montrent que les individus qui souffrent du TSPT ont moins de cortisol salivaire le matin, une augmentation des récepteurs glucocorticoïdes et une augmentation de niveaux de méthylation totale dans la région promoteur 1C du sang. Il semblerait aussi qu'un trauma vécu durant l'âge adulte soit plus significatif pour l'axe HPA, alors qu'un trauma durant l'enfance semblerait prendre le dessus pour les modifications épigénétiques. Ces résultats montrent que 1) les personnes souffrant du TSPT ont une activité HPA atténuée, 2) l'épigénétique joue un rôle différent chez les TSPT comparés aux patients abusés qui ont commis un suicide et 3) le temps du trauma a des effets significatifs pour l'axe HPA et les modifications épigénétiques.
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Brückmann, Christof [Verfasser], and Vanessa [Akademischer Betreuer] Nieratschker. "Epigenetic dysregulation in alcohol dependence and borderline personality disorder / Christof Brückmann ; Betreuer: Vanessa Nieratschker." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1198858958/34.
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Pape, Julius-Christopher [Verfasser], and Mathias [Akademischer Betreuer] Schmidt. "Novel epigenetic and genetic biomarker candidates in post-traumatic stress disorder / Julius-Christopher Pape ; Betreuer: Mathias Schmidt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1233966987/34.
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Cervera, Carles Laura. "Assessing the role of copy number variations, mitochondrial DNA and microRNAs in neurodegenerative disorders." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/668060.
Full textAbstract:
Les malalties neurodegeneratives són patologies complexes i progressives que afecten milions de persones a tot el món. Entre d’altres, la malaltia d’Alzheimer (MA), la malaltia de Parkinson (MP) i la demència frontotemporal (DFT) són les tres condicions més prevalents. Tot i l’extensiva recerca duta a terme, els esdeveniments moleculars que desencadenen aquestes patologies són encara desconeguts.
L’objectiu d’aquesta tesi és entendre el rol de determinats factors genètics i epigenètics en les malalties neurodegeneratives, a través de l’estudi de les reestructuracions genètiques, i la quantificació d’ADN mitocondrial circulant i espècies d’ARN no codificants.
Primerament, s’ha analitzat el patró de variació estructural del cromosoma 17q21.31, una de les regions més complexes i dinàmiques del genoma humà, i s’ha avaluat la seva contribució en la ben establerta associació entre l’haplotip H1 del gen MAPT i la MP, la paràlisi supranuclear progressiva (PSP), la degeneració corticobasal (DCB) i la demència amb cossos de Lewy (DCLewy). Els resultats obtinguts suggereixen que els polimorfismes de número de còpies dintre d’aquesta regió no són responsables de l’efecte H1. Tot i això, hem trobat una sobre-representació dels portadors H1 en el grup de pacients amb DCLewy, expandint d’aquesta manera la rellevància biològica de l’haplotip en les malalties neurodegeneratives.
També s’han examinat els nivells d’ADN mitocondrial circulant en líquid cefaloraquidi (LCR) i la seva utilitat com a indicador de la disfunció mitocondrial en el contínuum de la MA. Malgrat que la seva quantificació és fiable, la gran variabilitat interindividual entre els grups d’estudi limita la seva precisió i utilitat com a biomarcador diagnòstic.
Finalment, s’ha investigat el perfil d’expressió de microARNs, una classe de ARNs no codificants involucrats en la modulació post-transcripcional de l’expressió gènica, continguts en vesícules extracel·lulars (VEs) de LCR en DFT i altres síndromes relacionats. Es poden detectar nombrosos microARNs en VEs de LCR. També s’han identificat quatre microARNs amb un patró d’expressió específic en pacients diagnosticats amb síndromes DFT 4R-tau.Neurodegenerative diseases are complex and progressive disorders that affect millions of people worldwide. Among them, Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementia (FTD) are three of the most prevalent. In spite of extensive research, the molecular events triggering these pathologies remain elusive. This thesis aims at understanding the role of certain genetic and epigenetic factors in neurodegenerative diseases through the study of structural genetic rearrangements, and the measurement of circulating mitochondrial DNA and non-coding RNA species. We first analyzed the structural variation pattern of the chromosome 17q21.31, one of the most complex and dynamic regions of the human genome, and evaluated its contribution to the well-established MAPT H1 haplotype relationship with PD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB). Our results suggest that copy number polymorphisms within this region are not responsible for the H1 effect. However, we found a significant overrepresentation of H1 carriers in DLB patients, thus expanding the biological relevance of the haplotype in neurodegenerative disorders. We also examined the levels of circulating cell-free mitochondrial DNA in cerebrospinal fluid (CSF) and its utility as an indicator of mitochondrial dysfunction in the AD continuum. Although its measurement is reliable, the considerable inter-individual variability within groups limits its accuracy and usefulness as a diagnostic biomarker. Finally, we investigated the expression profile of microRNAs, a class of non-coding RNAs involved in the post-transcriptional modulation of gene expression, contained in extracellular vesicles (EVs) from CSF in FTD and other related syndromes. Numerous microRNAs can be detected within EVs from CSF. Moreover, we identified four microRNAs with a specific expression pattern in patients diagnosed with 4R-tau FTD syndromes.
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Esteves, Beatriz Rosmaninho. "Distúrbios alimentares: contributos da genética na anorexia nervosa." Bachelor's thesis, [s.n.], 2020. http://hdl.handle.net/10284/9661.
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Trabalho Complementar apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de licenciada em Ciências da NutriçãoOs distúrbios alimentares têm sido considerados doenças psiquiátrias influenciadas, principalmente, por fatores familiares e socioculturais. Etiopatologicamente multifatoriais, estas doenças afetam, principalmente, adolescentes e adultos jovens do sexo feminino. Nestes doentes, as alterações do comportamento alimentar desencadeiam alterações biológicas, psicológicas e sociais que estão frequentemente associadas a um aumento de morbilidade e de mortalidade. Deste grupo de doenças fazem parte a anorexia nervosa, a bulimia nervosa e o transtorno da compulsão alimentar periódica No Ocidente, estas doenças afetam cerca de 5% da população. A sua heterogeneidade subfenotípica, o número realtivamente reduzido de casos e a diversidade de fatores etiológicos tem dificultado a compreensão das causas moleculares destas doenças. No sentido de compreender a contribuição da genética para a elucidação da sua etiopatologia, o presente trabalho explora os principais fatores de risco para o desenvolvimento das doenças do comportamento alimentar, em particular os fatores de risco genético associados à anorexia nervosa. Apesar da diversidade de abordagens metodológicas utilizadas, até à presente, e tanto quanto é do nosso conhecimento, nenhum fator causal foi conclusivamente identificado. Contudo, globalmente, os resultados desses estudos não só suportam o envolvimento de fatores genéticos e epigenéticos no desenvolvimento dos distúrbios alimentares, como revelaram potenciais factores causais muito promissores e que, por isso, deverão continuar a ser investigados no futuro.
Eating disorders have been considered psychiatric diseases influenced mainly by familial and socio-cultural factors. As multifactorial diseases, they mainly affect female adolescents and young adults. In these patients, changes in eating behaviour trigger biological, psychological and social changes that are often associated with increased morbidity and mortality. This group of diseases includes anorexia nervosa, bulimia nervosa and binge eating disorder In the West, these diseases affect about 5% of the population. Its sub-phenotypic heterogeneity, the actually reduced number of cases and the diversity of etiological factors have made it difficult to understand the molecular causes of these diseases. In order to understand the contribution of genetics to the elucidation of its etiopathology, the present work explores the main risk factors for the development of diseases of eating behaviour, in particular the genetic risk factors associated with anorexia nervosa. Despite the diversity of methodological approaches used to date, to the best of our knowledge, no causal factors have been conclusively identified. However, globally, the results of these studies not only support the involvement of genetic and epigenetic factors in the development of eating disorders, but have also revealed potential very promising causal factors that should continue to be investigated in the future.
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Chatterjee, Snehajyoti. "Role of lysine acetyltransferase (KAT) activation in spatial memory : a new therapeutic approach for memory related disorders such as Alzheimer’s disease." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ092/document.
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La CREB Binding Protein (CBP) a une activité lysine acétyltransférase intrinsèque et fonctionne aussi comme un co-activateur transcriptionnel. L'activité acétyltransférase et la fonction de coactivateur transcriptionel sont toutes deux essentielles pour la formation de mémoire à long terme. De plus, la dérégulation de CBP a été observée dans des maladies neurodégénératives comme la maladie d'Alzheimer et la maladie de Huntington. L'objectif de ma thèse était d'étudier le rôle de la CBP et de son activation pharmacologique dans le cadre de la formation de la mémoire spatiale, une forme de mémoire qui est démantelé très tôt dans la MA. Les données obtenues à partir de ma thèse montrent que l'activation de la fonction acétyltransférase CBP par l’activateur CSP-TTK21 améliore les processus mnésiques chez des souris adultes normales et aussi dans un modèle murin de MA (THY-Tau22). Ainsi, la stratégie d’activation pharmacologique de l'activité acétyltransférase de CBP a un énorme potentiel pour une utilisation en tant qu'agent thérapeutique pour le traitement des maladies liées à l'altération de la mémoire tel que la maladie d'AlzheimerCREB Binding Protein (CBP) has an intrinsic lysine acetyltransferase activity and alsofunctions as a transcriptional co-activator. Both the acetyltransferase activity and the transcriptional co-activator function are critical for long-term memory formation. Importantly, CBP dysregulation has been observed in neurodegenerative conditions like in Alzheimer’s disease and Huntington’s disease. The focus of my thesis was to study the role of CBP and its activation by a new pharmacological tool, in the context of spatial memory formation, a form of memory that is very early dismantled in AD. Data obtained from my thesis clearly suggests that activation of CBP acetyltransferase function by small molecule activator CSP-TTK21 can improve memory related processes in healthy adult mice and also in a mouse model of AD, (THY-Tau22). Therefore, the strategy of pharmacological activation of CBP acetyltransferase activity has tremendous potential for use as therapeutics for the treatment of diseases related to memory impairment such as Alzheimer’s disease
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Conrad, Daniela [Verfasser]. "The Biology of Mental Health After Trauma : A Multi-Method Approach to Unravel the Genetics and Epigenetics of Posttraumatic Stress Disorder and its Treatment / Daniela Conrad." Konstanz : Bibliothek der Universität Konstanz, 2018. http://d-nb.info/1175879800/34.
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Scourzic, Laurianne. "Etude des mécanismes de coopération oncogénique impliquant TET2 dans les hémopathies malignes : exemples des coopérations avec DNMT3A et EZH2." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS046.
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Les protéines de la famille TET catalysent l'oxydation des 5-méthylcytosines (5mC) en 5-hydroxyméthylcytosines (5hmC) et jouent ainsi un rôle dans la régulation épigénétique de la transcription et dans le processus de déméthylation de l'ADN. Les interactions entre la méthylation de l'ADN et les autres marques épigénétiques sont encore mal connues.Des mutations inactivatrices du gène TET2 ont été décrites dans les hémopathies myéloïdes et lymphoïdes et l'inactivation conditionnelle (cKO) de ce gène évaluée chez la souris a permis d'identifier de multiples anomalies de l'hématopoïèse, ainsi que le développement tardif d'hémopathies myéloïdes. Cette latence importante suggère la nécessité d'évènements oncogéniques coopératifs pour la transformation hématopoïétique. Chez l'Homme, les mutations de TET2 sont observées en association avec de nombreuses autres mutations, et en particulier avec des mutations du gène DNMT3A impliqué dans la méthylation de novo des cytosines de l'ADN, et avec des mutations du gène EZH2 responsable de methylation de la lysine 27 de l'histone H3. Nous avons testé fonctionnellement ces associations en utilisant des modèles murins.L'utilisation d'un modèle de transplantation de moelle osseuse nous a permis d'identifier une coopération de l'inactivation de Tet2 et du mutant DNMT3AR882H dans la transformation des lignées myéloïdes et lymphoïde T, correspondant aux hémopathies humaines porteuses de ces mutations. Dans la transformation lymphoïde, nos données indiquent que la dérégulation de la méthylation entraine une surexpression du gène NOTCH1 et de l'activité de la voie de signalisation correspondante.L'analyse de souris invalidées de manière conditionnelle pour Tet2 et Ezh2 a montré que les souris correspondantes meurent d'aplasie médullaire, dont l'origine est imputée à la disparition de cellules souches hématopoïétiques capables de reconstituer l'hématopoïèse à long terme (LT-HSC). Ezh2 et Tet2 ont donc des rôles primordiaux dans le maintien de l'autorenouvellement des cellules souches hématopoïétiques, dont les mécanismes moléculaires, génétiques et épigénétiques restent à définirTET family proteins catalyzing the conversion of 5-methylcytosines (5mC) into 5-hydroxymethylcytosines (5hmC) are crucial for epigenetic regulation of transcription and for DNA demethylation. Interactions between DNA methylation and other epigenetic marks are not fully understood.TET2 inactivating mutations have been identified in both myeloid and lymphoid malignancies. The conditional inactivation (cKO) of this gene in mice highlights pleiotropic hematopoietic abnormalities as well as myeloid transformation at late stages. This latency suggest cooperativity between Tet2 and other oncogenic events during transformation. Human TET2 mutations are frequently found associated with other mutations, and more particularly with mutations in DNMT3A, involved in de novo methylation of cytosines and with mutations in EZH2, responsible for lysine 27 of histone H3 methylation. We decided to functionally assess these mutation associations in mice.Bone marrow transplantation of Tet2 inactivated and DNMT3AR882H mutated cells allowed us to identify myeloid and T-cell transformations, corresponding to human hematological disorders harboring these mutations. Our results on T-cell transformations clearly demonstrate that the deregulation of methylation leads to NOTCH1 overexpression and activation of the corresponding signaling pathway.Analyses of Tet2 and Ezh2 inactivated mice show that these Ezh2 Tet2 mice succumb to bone marrow exhaustion, attributed to long term hematopoietic stem cells (LT-HSC) disappearance. Ezh2 and Tet2 show major roles in LT-HSC maintenance whose molecular, genetic and epigenetic mechanism remains to be investigated
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Ozdarska, Katarzyna. "Synthèses d’inhibiteurs de HDAC et leurs tests biologiques (Cytotoxicité, HDAC inhibition)." Thesis, Reims, 2020. http://www.theses.fr/2020REIMS023.
Full textAbstract:
L’épigénétique représente les modifications de l’expression génique, sans altérer la séquence nucléique de l'ADN. L'un des mécanismes de régulation est le remodelage de la chromatine qui s’effectue via les histones acétyltransférases et les histones désacétylases (HDAC) permettant ou non la transcription de gènes. Une expression anormale des HDAC est corrélée à de nombreuses maladies (dépendance à l'alcool, inflammation ainsi que les maladies cardiovasculaires et neurodégénératives, cancers…). Il est primordial de cibler la sélectivité d’une isoforme parmi les 11 connues des HDAC zinc dépendantes pour éviter les effets secondaires. Le but de la recherche était de concevoir et de synthétiser de nouveaux composés, de vérifier leur activité inhibitrice vis-à-vis des HDAC de classe I ou II et leur cytotoxicité sur quatre lignées cellulaires: HaCaT, V79-4, SH-SY5Y et PC12. Ainsi, nous nous sommes concentrés sur les pharmacomodulations du ZBG, de l’espaceur et de la tête de molécules connues tels que le MS-275 (sélectif de la classe I des HDAC), les SAHA et TSA (espaceur en C5 ou C6) avec une forte activité inhibitrice vis-à-vis des HDAC, mais non sélectifs. Nous nous sommes concentrés sur les pharmacomodulations de l'HDACI connu modifiant le domaine de liaison au zinc ZBG (sulfonylhydrazide, catéchol), la nature de l’espaceur (alkyl, aryl) et le groupe de reconnaissance de surface (bis-aryl, adamantyl, indolopyridazinone). Une bibliothèque de 57 nouveaux composés a été créée en trois séries. Aucun d'entre eux n'a montré d'activité inhibitrice satisfaisante. Les composés sélectionnés n'ont pas montré d'activité cytotoxique sur les lignées de cellules neuronales. Sur la base de cette recherche, il est possible de créer de nouveaux composés dans la série indolopyridazinone afin de les testerEpigenetics represents changes in gene expression without altering the nucleic sequence of DNA. One of the main mechanisms of regulation of gene expression is chromatin remodeling via histone acetyltransferases and histone deacetylases (HDAC), which may or may not allow gene transcription. An abnormal expression of HDACs is correlated with many diseases (alcohol dependence, inflammation as well as cardiovascular and neurodegenerative diseases, cancers...). It is essential to target the selectivity of one isoform among the 11 known zinc-dependent HDACs to avoid side effects. The aim of the research was to design and synthesize new compounds, verify their inhibitory activity against class I or II HDACs and their cytotoxicity on four cell lines: HaCaT, V79-4, SH-SY5Y and PC12. We focused on the pharmacomodulations of ZBG, the linker and the cap of known molecules such as MS-275 (selective for class I of HDACs), SAHA and TSA (spacer in C5 or C6) with a strong inhibitory activity towards HDACs, but not selective. We concentrated on the pharmacomodulations of known HDACI modifying the zinc binding domain (sulfonylhydrazide, catechol), the nature of the spacer (alkyl, aryl) and the surface recognition group (bis-aryl, adamantyl, indolopyridazinone). A library of 57 new compounds was designed in three series. None of them showed satisfactory inhibitory activity. The selected compounds did not show cytotoxic activity on neuronal cell lines. Based on this research, it is possible to create new compounds in the indolopyridazinone series in order to test them
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Cantacorps, Centellas Lídia 1991. "Effects of maternal binge alcohol consumption on emotional, cognitive and addictive behaviour in mice." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/667941.
Full textAbstract:
Maternal alcohol binge drinking during pregnancy can be deleterious for the developing foetus, leading to a wide range of long-lasting morphological and neurobehavioural disabilities known as foetal alcohol spectrum disorders, associated with a higher risk of developing substance use disorders later in life. We sought to assess the effects of prenatal and postnatal alcohol exposure on cognitive, emotional, motor and addictive behaviour in mice and its underlying molecular mechanisms. Pregnant C57BL/6 female mice underwent a procedure to model alcohol binge drinking either during gestation or throughout both the gestation and lactation periods. Then, male offspring were assessed for their behaviour at adulthood. Binge alcohol exposure during early brain development induces cognitive deficits, increased anxiety-like behaviour, motor coordination impairments, and age-dependent locomotor activity alterations. Behavioural effects are associated with an upregulation of pro-inflammatory signalling, gliosis, neuronal death, myelin impairments and epigenetic modifications in the prefrontal cortex and hippocampus. Furthermore, early alcohol exposed mice show alterations in brain network connectivity. Curcumin treatment ameliorates anxiety and cognitive dysfunctions, and rescues alcohol-induced neuroinflammation. In addition, mice exposed to alcohol in utero and postnatally show increased susceptibility to later alcohol and cocaine intake compared with their counterparts. Molecular analyses of the prefrontal cortex and striatum of these animals suggest alterations in the glutamatergic excitability within the mesocorticolimbic reward system following cocaine-induced reinstatement. Altogether, our results reveal that maternal binge-like alcohol consumption induces molecular alterations in offspring’s brain that may underlie the long-lasting impairments in offspring’s behaviour.El consum maternal d’alcohol en afartament durant l’embaràs pot resultar perjudicial per al fetus en desenvolupament, donant lloc a una àmplia gamma de discapacitats físiques i mentals conegudes com a trastorns de l’espectre alcohòlic fetal que persisteixen al llarg de la vida i estan associades a un major risc de desenvolupar trastorns d’ús de substàncies en el futur. En aquesta tesi hem tractat d’avaluar els efectes de l’exposició prenatal i postnatal a l’alcohol en la conducta cognitiva, emocional, motora i addictiva en ratolins i els mecanismes moleculars subjacents a aquests. Les femelles de ratolins C57BL/6 embarassades van ser sotmeses a un procediment per modelar el consum d’alcohol en afartament durant la gestació o bé, al llarg dels períodes de gestació i lactància. A continuació es va avaluar el comportament de la descendència masculina a l’edat adulta. S’ha observat que l’exposició d’alcohol en afartament durant el desenvolupament cerebral indueix dèficits cognitius, augment de l’ansietat, alteracions de coordinació motora i de l’activitat locomotora en funció de l’edat. Els efectes del comportament estan associats a un increment de la senyalització proinflamatòria, gliosi, mort neuronal, deteriorament de la mielina i modificacions epigenètiques en el còrtex prefrontal i l’hipocamp, així com també alteracions en la connectivitat de la xarxa neuronal. El tractament de curcumina alleuja l’ansietat i les disfuncions cognitives, i restableix la neuroinflamació induïda per l’alcohol. A més, els ratolins exposats a l’alcohol durant la gestació i la lactància mostren una major susceptibilitat a la ingesta posterior d’alcohol i cocaïna en comparació amb els seus homòlegs. Els anàlisis moleculars de l’escorça prefrontal i de l’estriat d’aquests animals suggereixen la presència d’alteracions en l’excitabilitat glutamatèrgica en el sistema de recompensa mesocorticolimbic després de la recaiguda induïda per cocaïna. En conjunt, els nostres resultats indiquen que el consum maternal d’alcohol en afartament provoca alteracions moleculars en el cervell de la descendència com a mecanisme subjacent a les alteracions relatives al comportament persistents.
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Desai, Megha. "Structural and Functional Characterization of the MBD2-NuRD Co-Repressor Complex." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3617.
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The MBD2-NuRD co-repressor complex is an epigenetic regulator of the developmental silencing of embryonic and fetal β-type globin genes in adult erythroid cells as well as aberrant methylation-dependent silencing of tumor suppressor genes in neoplastic diseases. Biochemical characterization of the MBD2-NuRD complex in chicken erythroid cells identified RbAp46/48, HDAC1/2, MTA1/2/3, p66α/β, Mi2α/β and MBD2 to comprise this multi-protein complex.
In the work presented in Chapter 2, we have pursued biophysical and molecular studies to describe a previously uncharacterized domain of human MBD2 (MBD2IDR). Biophysical analyses show that MBD2IDR is an intrinsically disordered region (IDR). Despite this inherent disorder, MBD2IDR increases the overall binding affinity of MBD2 for methylated DNA. MBD2IDR also recruits the histone deacetylase core components (RbAp48, HDAC2 and MTA2) of NuRD through a critical area of contact requiring two contiguous amino acid residues, Arg286 and Leu287. Mutation of these critical residues abrogates interaction of MBD2 with the histone deacetylase core and impairs the ability of MBD2 to repress the methylated tumor suppressor gene Prostasin in MDA-MB-435 breast cancer cells. These findings expand our knowledge of the multi-dimensional interactions of the MBD2-NuRD complex that govern its function.
In Chapter 3, we have discussed a novel mechanism for MBD2-mediated silencing of the fetal γ-globin gene. Through microarray expression analyses in adult erythroid cells of MBD2-/- mice, we identified ZBTB32 and miR-210 as downstream targets of MBD2. Over-expression of ZBTB32 and miR-210 in adult erythroid cells causes increased expression of the silenced fetal γ-globin gene. Thus, our results indicate that MBD2 may regulate γ-globin gene expression indirectly though ZBTB32 and miR-210 in adult erythroid cells.
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Mao, Wenjie. "Molecular Players in Preserving Excitatory-Inhibitory Balance in the Brain." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/947.
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Information processing in the brain relies on a functional balance between excitation and inhibition, the disruption of which leads to network destabilization and many neurodevelopmental disorders, such as autism spectrum disorders. One of the homeostatic mechanisms that maintains the excitatory and inhibitory balance is called synaptic scaling: Neurons dynamically modulate postsynaptic receptor abundance through activity-dependent gene transcription and protein synthesis. In the first part of my thesis work, I discuss our findings that a chromatin reader protein L3mbtl1 is involved in synaptic scaling. We observed that knockout and knockdown of L3mbtl1 cause a lack of synaptic downscaling of glutamate receptors in hippocampal primary neurons and organotypic slice cultures. Genome-wide mapping of L3mbtl1 protein occupancies on chromatin identified Ctnnb1 and Gabra2 as downstream target genes of L3mbtl1-mediated transcriptional regulation. Importantly, partial knockdown of Ctnnb1 by itself prevents synaptic downscaling. Another aspect of maintaining E/I balance centers on GABAergic inhibitory neurons. In the next part of my thesis work, we address the role of the scaffold protein Shank1 in excitatory synapses onto inhibitory interneurons. We showed that parvalbumin-expressing interneurons lacking Shank1 display reduced excitatory synaptic inputs and decreased levels of inhibitory outputs to pyramidal neurons. As a consequence, pyramidal neurons in Shank1 mutant mice exhibit increased E/I ratio. This is accompanied by a reduced expression of an inhibitory synapse scaffolding protein gephyrin. These results provide novel insights into the roles of chromatin reader molecules and synaptic scaffold molecules in synaptic functions and neuronal homeostasis.
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Bouarab, Chloe. "Modifications post-traductionnelles des histones au sein du circuit hippocampo-amygdalien déterminant le passage d'une mémoire de peur normale à une mémoire traumatique." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0261/document.
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Les altérations mnésiques associées au trouble de stress post-traumatique (TSPT) constituent un aspect fondamental de la symptomatologie de cette pathologie. Cette altération qualitative de la mémoire inclut à la fois une hypermnésie, c’est-à-dire une intensification de la mémoire vis-à-vis du coeur de l’événement traumatique, et une amnésie de type déclaratif pour les éléments contextuels péri-traumatiques. Les données chez l’Homme suggèrent que ces altérations mnésiques pourraient être sous-tendues par une hyper-activation amygdalienne et un dysfonctionnement hippocampique, respectivement. Cependant, les bases neurobiologiques, et en particulier moléculaires, du TSPT restent largement méconnues. Un modèle comportemental développé chez la souris au laboratoire et basé sur un conditionnement aversif permet précisément de comparer une mémoire de peur normale, c’est-à-dire « contextualisée » et adaptée, à une mémoire pathologique de type TSPT, c’est-à-dire « décontextualisée » et focalisée sur un élément saillant du trauma. Dans la mesure où il a été montré que le développement d’une mémoire de peur contextuelle implique certaines modifications épigénétiques spécifiques, nos travaux ont eu pour objectif de déterminer les altérations des modifications post-traductionnelles d’histones qui sous-tendent le développement d’une mémoire traumatique au lieu d’une mémoire de peur normale. Nos résultats révèlent (1) que des profils spécifiques différents des états d’acétylation/méthylation de l’histone H3 dans le réseau hippocampo-amygdalien sont associés à une mémoire de peur normale et à une mémoire traumatique de type TSPT. Spécifiquement, une mémoire de peur normale est associée à une forte acétylation de H3K9 hippocampique, tandis qu’une mémoire traumatique de type TSPT s’accompagne d’une hyperméthylation de H3K9 dans l’hippocampe, traduisant une répression transcriptionnelle, ainsi que d’une diminution de la tri-méthylation de H3K27 dans l’amygdale latérale, caractéristique d’une activation transcriptionnelle. De plus, nos travaux montrent (2) qu’une modulation pharmacologique de la balance des états d’acétylation/méthylation de H3K9 dans l’hippocampe permet de promouvoir ou de prévenir le développement d’une mémoire traumatique. Enfin, (3) une dernière série d’expériences révèle (i) qu’un stress prénatal est un facteur de risque au développement d’une mémoire traumatique, (ii) que cette dernière est associée à des profils épigénétiques spécifiques, et (iii) qu’une telle vulnérabilité peut se transmettre de manière intergénérationnelleMemory alterations associated with post-traumatic stress disorder (PTSD) are a fundamental feature of this pathology. PTSD is characterized both by hypermnesia for simple salient trauma-related stimuli and amnesia for peri-traumatic contextual cues. In humans, this disorder is associated with hippocampal hypofunction and amygdalar hyperfunction, which may underlie such paradoxical memory pattern. However, neurobiological bases of PTSD, particularly at the molecular level, remain largely unknown. A behavioral model based on aversive conditioning was developed in mice by our team. This model allows the comparison between a normal, i.e. “contextualized” and adaptive, fear memory, and a PTSD-like pathological fear memory, i.e. “decontextualized” and focused on a salient cue of the trauma. Since specific epigenetic alterations have been involved in the development of contextual fear memory, our aim was the identification of the alterations in post-translational histone modifications underlying the development of traumatic memory instead of normal fear memory. Our results first reveal that normal and PTSD-like fear memory are associated with distinct acetylation/methylation profiles of histone H3 in the hippocampal-amygdalar network. Specifically, we show that, compared to normal fear memory, PTSD-like memory is associated with a switch from H3K9 hyperacetylation (marker of transcriptional activation) to H3K9 hypermethylation (marker of transcriptional repression) in hippocampal CA1, as well as a significant reduction of H3K27 trimethylation, which results in an increased transcription, in the lateral amygdala. Second, we show that the pharmacological manipulation of the acetylation/methylation balance of H3K9 in the hippocampus can prevent or promote the development of PTSD-like memory. Finally, a last series of experiments shows that (i) prenatal stress is a risk factor for the development of PTSD-like memory, (ii) which is associated with specific epigenetic alterations and (iii) that such vulnerability to stress can be transmitted to subsequent generations
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Pineda, i. Cirera Laura. "Genètica i epigenètica de les addiccions i trastorns comòrbids." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/672726.
Full textAbstract:
Aquesta Tesi té com a objectiu principal contribuir a l’estudi i a la identificació de factors genètics i epigenètics de susceptibilitat a les addiccions i a trastorns comòrbids, tant en humans com en models animals. Els objectius concrets d’aquest treball són els següents:
CAPÍTOL 1. Estudi de factors genètics de risc a l’addicció a drogues identificats prèviament.
1.1. Realització d’un estudi de rèplica d’associacions a la dependència de drogues, i de cocaïna en particular, prèviament identificades en estudis d’associació genètica a escala genòmica.
1.2. Avaluació de l’efecte d’NFAT5, un gen candidat a l'addicció a cocaïna descrit prèviament pel grup, sobre la síntesi de la dopamina a través de la regulació de l’expressió del gen DDC en dues línies cel·lulars neurals dopaminèrgiques.
CAPÍTOL 2. Identificació de factors epigenètics de susceptibilitat a l’addicció a les drogues i al
menjar.
2.1. Estudi de la contribució a la dependència de drogues de variants genètiques amb un efecte sobre la metilació específica d’al·lel (ASM).
2.2. Identificació de variants genètiques de susceptibilitat a la dependència de drogues que poden
alterar el lloc d’unió de miRNAs, i posterior avaluació funcional de les variants identificades.
2.3. Exploració dels perfils transcriptòmics (mRNAs i miRNAs) i metilòmics en un model de ratolí
d’addicció al menjar.
CAPÍTOL 3. Identificació de factors epigenètics de susceptibilitat a trastorns comòrbids a l’addicció
a les drogues.
3.1. Exploració de la contribució de variants genètiques amb un efecte en l’ASM al trastorn per
dèficit d'atenció amb hiperactivitat (TDAH).
3.2. Anàlisi de la funció de C2orf82 al cervell i de la seva contribució al TDAH: determinació de l’expressió del gen en diferents àrees cerebrals de ratolí i caracterització fenotípica d’un model murí genoanul·lat.
3.3. Avaluació de l’efecte pleotròpic de variants genètiques que presenten ASM en diferents trastorns psiquiàtrics.Addiction is a complex neuropsychiatric disorder characterized by compulsive and uncontrolled use of an addictive stimulus such as drugs of abuse or food. Its etiology involves genetic and environmental factors, with epigenetics as the interplay between them. Although family and twin studies have estimated a high contribution of genetics to the disease, the underlying mechanisms remain largely unknown. In addition, multiple studies have shown that addiction is highly comorbid with other psychiatric disorders, which can be explained, at least in part, by shared genetics. The work presented in this Doctoral Thesis has contributed to the study and identification of genetic and epigenetic factors underlying drug and food addiction, as well as comorbid disorders. First, we have replicated a variant previously identified in a genome wide association study for drug dependence and we have discarded that NFAT5, a candidate gene for cocaine dependence, modulates dopamine synthesis by regulating DDC expression in dopaminergic neural cell lines. Subsequently, we focused on the identification of genes and epigenetic risk factors for drug and food addiction. We identified three variants associated with drug addiction that alter the methylation of CpG sites or the binding of miRNAs, pinpointing CTNNBL1, SCP2, ECHDC2 and PLCB1 as candidate genes for the disorder. Furthermore, we have identified several mRNAs and miRNAs that are differentially expressed in two brain areas of mice with extreme behaviours towards food addiction-like phenotype (vulnerable and resilient), some of these changes explained by promoter methylation alterations. Then, we have identified multiple variants affecting the methylation of CpG sites associated with ADHD. Some of these variants have an impact on the expression of three genes, ARTN, PIDD1 and C2orf82, pointing them as candidates to contribute to the disorder. For the C2orf82 gene, we have explored its expression in the mouse brain, obtaining the highest expression in the nucleus accumbens, and we have also phenotyped a knockout mouse model, observing hypolocomotion, impulsivity and lower cocaine motivation. Finally, we have identified multiple variants that affect brain methylation and expression of eight genes with pleiotropic effects on several psychiatric disorders.
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Ziegler, Christiane. "Epigenetic Mechanisms in the Pathogenesis and Therapy of Anxiety Disorders." Doctoral thesis, 2016. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-146815.
Full textAbstract:
Anxiety disorders (AD) are common, disabling mental disorders, which constitute the most prevalent mental health condition conveying a high individual and socioeconomic burden. Social anxiety disorder (SAD), i.e. fear in social situations particularly when subjectively scrutinized by others, is the second most common anxiety disorder with a life time prevalence of 10%. Panic disorder (PD) has a life time prevalence of 2-5% and is characterized by recurrent and abrupt surges of intense fear and anticipatory anxiety, i.e. panic attacks, occurring suddenly and unexpected without an apparent cue. In recent years, psychiatric research increasingly focused on epigenetic mechanisms such as DNA methylation as a possible solution for the problem of the so-called “hidden heritability”, which conceptualizes the fact that the genetic risk variants identified so far only explain a small part of the estimated heritability of mental disorders. In the first part of this thesis, oxytocin receptor (OXTR) gene methylation was investigated regarding its role in the pathogenesis of social anxiety disorder. In summary, OXTR methylation patterns were implicated in different phenotypes of social anxiety disorder on a categorical, neuropsychological, neuroendocrinological as well as on a neural network level. The results point towards a multilevel role of OXTR gene hypomethylation particularly at one CpG site (CpG3, Chr3: 8 809 437) within the protein coding region of the gene in SAD. The second part of the thesis investigated monoamine oxidase A (MAOA) gene methylation regarding its role in the pathogenesis of panic disorder as well as – applying a psychotherapy-epigenetic approach – its dynamic regulation during the course of cognitive behavioural therapy (CBT) in PD patients. First, MAOA hypomethylation was shown to be associated with panic disorder as well as with panic disorder severity. Second, in patients responding to treatment MAOA hypomethylation was shown to be reversible up to the level of methylation in healthy controls after the course of CBT. This increase in MAOA methylation along with successful psychotherapeutic treatment was furthermore shown to be associated with symptom improvement regarding agoraphobic avoidance in an independent replication sample of non-medicated patients with PD. Taken together, in the future the presently identified epigenetic patterns might contribute to establishing targeted preventive interventions and personalized treatment options for social anxiety disorder or panic disorder, respectivelyAngsterkrankungen sind die häufigsten psychischen Erkrankungen, welche in hohem Maße den Alltag der Betroffenen beeinträchtigen und eine große sozioökonomische Belastung darstellen. Eine der häufigsten Formen von Angsterkrankungen bildet die soziale Phobie, d.h. die Angst vor sozialen Situationen, in denen man im Mittelpunkt der Aufmerksamkeit steht, mit einer Lebenszeit-Prävalenz von circa 10%. Die Panikstörung, charakterisiert durch das wiederholte und unerwartete Auftreten von Panikattacken, ist eine weitere Form der Angsterkrankungen mit einer Lebenszeit-Prävalenz von circa 2-5%. Epigenetische Mechanismen, wie zum Beispiel die DNA Methylierung, rücken in den letzten Jahren immer weiter in den Fokus der psychiatrischen Forschung. Hier werden sie als eine mögliche Lösung für das Problem der „hidden heritability“ (versteckte Heritabilität) angesehen. Im ersten Teil dieser Arbeit wurde die DNA Methylierung des Oxytozinrezeptorgens (OXTR) hinsichtlich ihrer Rolle in der Pathogenese der sozialen Phobie untersucht. Hierbei konnte eine verringerte Methylierung des Gens, speziell an einem CpG-Dinukleotid (CpG3, Chr3: 8 809 437) innerhalb der protein-kodierenden Genregion, auf verschiedenen Ebenen mit der Erkrankung an sozialer Phobie, dimensionalen Maßen der Erkrankungsschwere sowie der Stressverarbeitung auf neuro-endokrinologischer und neuronaler Ebene in Verbindung gebracht werden. Der zweite Teil dieser Arbeit beschäftigt sich mit der Rolle von DNA Methylierungsmustern des Monoaminooxidase A (MAOA) Gens in der Pathogenese und der Therapie der Panikstörung. Zum einen konnte gezeigt werden, dass eine verringerte MAOA Methylierung mit dem Auftreten von Panikstörung sowie mit einer erhöhten Symptomschwere assoziiert ist. Zum anderen zeigten Patienten, welche auf eine kognitive Verhaltenstherapie (KVT) ansprachen, eine signifikante Erhöhung der MAOA Methylierung nach der Therapie, welche zusätzlich in einer unabhängigen Stichprobe mit einer Verringerung der Symptomschwere assoziiert war. Diese Veränderung zeigte sich jedoch nicht in Patienten, welche nicht auf die KVT ansprachen. Zusammenfassend können beide im Rahmen dieser Arbeit untersuchten epigenetischen Muster und deren Rolle in der Pathogenese der sozialen Phobie sowie der Panikstörung zur Etablierung personalisierter Therapiemöglichkeiten wie auch targetierter präventiver Interventionen beitragen
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Chen, Yuanyuan. "Epigenetic alteration by prenatal alcohol exposure in developing mouse hippocampus and cortex." Thesis, 2014. http://hdl.handle.net/1805/5810.
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Indiana University-Purdue University Indianapolis (IUPUI)Fetal alcohol spectrum disorders (FASD) is the leading neurodevelopment deficit in children born to women who drink alcohol during pregnancy. The hippocampus and cortex are among brain regions vulnerable to alcohol-induced neurotoxicity, and are key regions underlying the cognitive impairment, learning and memory deficits shown in FASD individuals. Hippocampal and cortical neuronal differentiation and maturation are highly influenced by both intrinsic transcriptional signaling and extracellular cues. Epigenetic mechanisms, primarily DNA methylation and histone modifications, are hypothesized to be involved in regulating key neural development events, and are subject to alcohol exposure. Alcohol is shown to modify DNA methylation and histone modifications through altering methyl donor metabolisms. Recent studies in our laboratory have shown that alcohol disrupted genome-wide DNA methylation and delayed early embryonic development. However, how alcohol affects DNA methylation in fetal hippocampal and cortical development remains elusive, therefore, will be the theme of this study. We reported that, in a dietary alcohol-intake model of FASD, prenatal alcohol exposure retarded the development of fetal hippocampus and cortex, accompanied by a delayed cellular DNA methylation program. We identified a programed 5-methylcytosine (5mC) and 5-hydroxylmethylcytosine (5hmC) cellular and chromatic re-organization that was associated with neuronal differentiation and maturation spatiotemporally, and this process was hindered by prenatal alcohol exposure. Furthermore, we showed that alcohol disrupted locus-specific DNA methylation on neural specification genes and reduced neurogenic properties of neural stem cells, which might contribute to the aberration in neurogenesis of FASD individuals. The work of this dissertation suggested an important role of DNA methylation in neural development and elucidated a potential epigenetic mechanism in the alcohol teratogenesis.
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Moser, Dirk [Verfasser]. "Linking genetic variation and epigenetic modification : functional promoter analysis of SCL12A6 and NR3C1, two candidate genes involved in the pathogenesis of mood disorders / von Dirk Alexander Moser." 2008. http://d-nb.info/991617517/34.
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Jeremian, Richie. "Epigenetic Studies of Bipolar Disorder." Thesis, 2014. http://hdl.handle.net/1807/65557.
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Bipolar disorder is a psychiatric illness characterized by recurrent fluctuations in mood and increased risk of suicide. Twin and family studies have identified the highly heritable nature of the disorder, but the limitations of the current DNA-centric paradigm underscore the need for a new perspective to gain a clearer understanding of its basis. This project investigates various facets of bipolar disorder from an epigenetic standpoint. We used mass spectrometry-based mapping of individual DNA modification differences of the brain-derived neurotrophic factor gene. Moreover, the epigenetic basis of suicidal behaviour in bipolar disorder was investigated using DNA methylation microarrays. We also used a newly-developed enrichment technique, mTAG, to interrogate chromosome-wide DNA modification profiles using tiling microarrays in post-mortem brains of bipolar disease patients and controls. Findings from these experiments highlight observable features of epigenomes of patients affected with mood disorders, and may further the understanding of the molecular origin of psychiatric diseases.
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Legault, Lisa-Marie. "Identification de dérèglements épigénétiques embryonnaires associés à une exposition prénatale à l’alcool pendant la période préimplantatoire." Thèse, 2017. http://hdl.handle.net/1866/20410.
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"The Epigenome: Possible Mechanisms by which Early Life Stress May Prime Vulnerability towards Substance Use Disorder." Doctoral diss., 2015. http://hdl.handle.net/2286/R.I.34795.
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abstract: Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS.Dissertation/Thesis
Doctoral Dissertation Psychology 2015
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Chen, Siying. "Integration of Functional Genomic Data in Genetic Analysis." Thesis, 2021. https://doi.org/10.7916/d8-snjy-r856.
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Identifying disease risk genes is a central topic of human genetics. Cost-effective exome and whole genome sequencing enabled large-scale discovery of genetic variations. However, the statistical power of finding new risk genes through rare genetic variation is fundamentally limited by sample sizes. As a result, we have an incomplete understanding of genetic architecture and molecular etiology of most of human conditions and diseases. In this thesis, I developed new computational methods that integrate functional genomics data sets, such as epigenomic profiles and single-cell transcriptomics, to improve power for identifying genetic risks and gain more insights on etiology of developmental disorders. The overall hypothesis that disease risk genes contributing to developmental disorders are bottleneck genes under normal development and subject to precise transcriptional regulations to maintain spatiotemporal specific expression during development. In this thesis I describe two major research projects. The first project, Episcore, predicts haploinsufficient genes based on a large integrated epigenomic profiles from multiple tissues and cell lines by supervised machine learning methods. The second one, A-risk, predicts plausibility of being risk genes of autism spectrum disorder based on single-cell RNA-seq data collected in human fetal midbrain and prefrontal cortex. Both methods were shown to be able to improve gene discovery in analysis of de novo mutations in developmental disorders. Overall, my thesis represents an effort to integrate functional genomics data by machine learning to facilitate both discovery and interpretation of genetic studies of human diseases. We believe that such integrative analysis can help us better understand genetic variants and disease etiology.
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Haue, Shui-sang, and 薛水上. "A study of malignant transformation in Patients with potentially malignant oral mucosal disorders and the expression of inhibitors of apoptosis (IAP) family in oral carcinogenesis and its implication with p53 and epigenetics." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/94220336478708176583.
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博士高雄醫學大學
牙醫學研究所博士班
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It is generally accepted that the development of cancer in the oral mucosa is preceded by an identifiable non-invasive precursor lesion. The aim of the present thesis in part I was to estimate the rate and the time to transformation in a group of patients from southern Taiwan with potentially malignant oral epithelial lesions. The follow-up time is defined as the duration between the onset of the initial diagnosis and the occurrence of confirmed oral cancer. A total of 1458 patients with histological diagnoses of various premalignant oral lesions were followed up between 1991 and 2001. The average age at initial diagnosis was 47.45±13.55 years. The histological diagnoses were divided into six catergories: epithelial dysplasia with hyperkeratosis/epithelial hyperplasia (8.85%); epithelial dysplasia with oral submucous fibrosis (2.54%); oral submucous fibrosis (27.57%); hyperkeratosis/epithelial hyperplasia (29.01%); lichen planus (9.80%) and verrucous hyperplasia ( 22.22%). Within the cohort of 1458 patients, 44 (3.02%) patients progressed to oral cancer in the same site as the initial lesions with an overall transformation rate of 5.61% and a mean follow-up time of 42.64±31.58 months. Eight of the 166 patients with dysplastic lesions and 15 of 423 patients with hyperkeratosis/epithelial hyperplasia progressed to malignancy. The other patients with malignant transformation originated from various pre-cancerous oral lesions and conditions (oral submucous fibrosis, 8 of 402; lichen planus, 3 of 143; verrucous hyperplasia, 10 of 324). Apoptosis (programmed cell death) is regulated by a number of inhibitory or stimulatory factor. One such family of antiapoptotic proteins is the inhibitors of apoptosis proteins (IAPs). To date, eight members of the IAP family have been described: cIAP1 (HIAP2, MIHB), cIAP2 (HIAP1, MIHC), XIAP (MIHA, hILP), survivin, NAIP, LIVIN (ML-IAP, KIAP), ILP2, and BRUCE (apollon). The best characterized IAP members are survivin, XIAP, cIAP1, cIAP2 and NAIP. The objective of the present thesis in part II was to investigate the expression of the inhibitiors of apoptosis (IAP) family during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal-pouch squamous-cell carcinogenesis and in human oral pre-malignant and malignant epithelial lesions and its implication with p53 and epigenetics. Survivin and cIAP2 ptoteins and mRNA were not detected in any untreated and mineral oil treated pouch-tissue, but they were detected in all specimens of 3-, 7- and 14 weeks DMBA treated pouch-tissue. XIAP, cIAP1 and NAIP were were detected in all specimens of untreated, mineral oil treated, 3-, 7- and 14 weeks DMBA treated pouch-tissue. p53 was not detected in any untreated and mineral oil treated pouch-tissue, but it was detected in all specimens of 3-, 7- and 14 weeks DMBA treated pouch-tissue. These five members of IAP family and p53 proteins were detected in all different human premalignant lesions and their malignant transformation cancerous lesions. The results of this study demonstrate the association between IAPs and p53 expression in this experimental model system for oral carcinogenesis and in human oral carcinogenesis, although their exact interactions remain to be clarified. Based on the methylation assay of these five members of IAP family, it reveals these IAPs control by epigenetic mechanism. In conclusion, the rate and the time to malignant transformation across a spectrum of potentially malignant oral epithelial lesions have been established in a Chinese population in Taiwan. This long-term study of 1458 pre-cancerous patients indicates that the management of oral premalignancy includes careful follow up. To understand the IAP family expression in oral carcinogenesis indicate that the potential of targeting strategies as novel therapeutic tools for oral squamous-cell carcinomas.
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McCain, Travis William. "Vitamin D Inhibits Expression of Protein Arginine Deiminase 2 and 4 in Experimental Autoimmune Encephalomoyelitis Model Of Multiple Sclerosis." Thesis, 2014. http://hdl.handle.net/1805/6018.
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Indiana University-Purdue University Indianapolis (IUPUI)Multiple sclerosis (MS) is a disabling disease that afflicts an estimated two million people worldwide. The disease is characterized by degradation of the myelin sheath that insulates neurons of the central nervous system manifesting as a heterogeneous collection of symptoms. Two enzymes, protein arginine deaminases type 2 and 4 (PAD2 and PAD4) have been implicated to play an etiologic role in demyelination and neurodegeneration by catalyzing a post-translational modification of arginine peptide residues to citrulline. The pathogenesis of MS is poorly understood, though vitamin D deficiency is a well-associated risk factor for developing the disorder. Using the experimental autoimmune encephalomyelitis (EAE) model of MS we demonstrate vitamin D treatment to attenuate over-expression of PAD 2 and 4 in the brain and spine during EAE. In addition, we identify two molecules produced by peripheral immune cells, IFNɣ and IL-6, as candidate signaling molecules that induce PAD expression in the brain. We demonstrate vitamin D treatment to inhibit IFNɣ mediated up regulation of PAD2 and PAD4 both directly within the brain and by modulating PAD-inducing cytokine production by infiltrating immune cells. These results provide neuroprotective rational for the supplementation of vitamin D in MS patients. More importantly, these results imply an epigenetic link between vitamin D deficiency and the pathogenesis of MS that merits further investigation.