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Wu, Xin, David A. Galbraith, Paramita Chatterjee, Hyeonsoo Jeong, Christina M. Grozinger, and Soojin V. Yi. "Lineage and Parent-of-Origin Effects in DNA Methylation of Honey Bees (Apis mellifera) Revealed by Reciprocal Crosses and Whole-Genome Bisulfite Sequencing." Genome Biology and Evolution 12, no. 8 (2020): 1482–92. http://dx.doi.org/10.1093/gbe/evaa133.
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Abstract Parent-of-origin methylation arises when the methylation patterns of a particular allele are dependent on the parent it was inherited from. Previous work in honey bees has shown evidence of parent-of-origin-specific expression, yet the mechanisms regulating such pattern remain unknown in honey bees. In mammals and plants, DNA methylation is known to regulate parent-of-origin effects such as genomic imprinting. Here, we utilize genotyping of reciprocal European and Africanized honey bee crosses to study genome-wide allele-specific methylation patterns in sterile and reproductive individuals. Our data confirm the presence of allele-specific methylation in honey bees in lineage-specific contexts but also importantly, though to a lesser degree, parent-of-origin contexts. We show that the majority of allele-specific methylation occurs due to lineage rather than parent-of-origin factors, regardless of the reproductive state. Interestingly, genes affected by allele-specific DNA methylation often exhibit both lineage and parent-of-origin effects, indicating that they are particularly labile in terms of DNA methylation patterns. Additionally, we re-analyzed our previous study on parent-of-origin-specific expression in honey bees and found little association with parent-of-origin-specific methylation. These results indicate strong genetic background effects on allelic DNA methylation and suggest that although parent-of-origin effects are manifested in both DNA methylation and gene expression, they are not directly associated with each other.
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Lefebvre, L., S. Viville, S. C. Barton, F. Ishino, and M. A. Surani. "Genomic Structure and Parent-of-Origin-Specific Methylation of Peg1." Human Molecular Genetics 6, no. 11 (1997): 1907–15. http://dx.doi.org/10.1093/hmg/6.11.1907.
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Golden, Lisa C., Yuichiro Itoh, Noriko Itoh, et al. "Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes." Proceedings of the National Academy of Sciences 116, no. 52 (2019): 26779–87. http://dx.doi.org/10.1073/pnas.1910072116.
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Many autoimmune diseases are more frequent in females than in males in humans and their mouse models, and sex differences in immune responses have been shown. Despite extensive studies of sex hormones, mechanisms underlying these sex differences remain unclear. Here, we focused on sex chromosomes using the “four core genotypes” model in C57BL/6 mice and discovered that the transcriptomes of both autoantigen and anti-CD3/CD28 stimulated CD4+T lymphocytes showed higher expression of a cluster of 5 X genes when derived from XY as compared to XX mice. We next determined if higher expression of an X gene in XY compared to XX could be due to parent-of-origin differences in DNA methylation of the X chromosome. We found a global increase in DNA methylation on the X chromosome of paternal as compared to maternal origin. Since DNA methylation usually suppresses gene expression, this result was consistent with higher expression of X genes in XY cells because XY cells always express from the maternal X chromosome. In addition, gene expression analysis of F1 hybrid mice from CAST × FVB reciprocal crosses showed preferential gene expression from the maternal X compared to paternal X chromosome, revealing that these parent-of-origin effects are not strain-specific. SJL mice also showed a parent-of-origin effect on DNA methylation and X gene expression; however, which X genes were affected differed from those in C57BL/6. Together, this demonstrates how parent-of-origin differences in DNA methylation of the X chromosome can lead to sex differences in gene expression during immune responses.
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Sandovici, Ionel, Sacha Kassovska-Bratinova, J. Concepción Loredo-Osti, et al. "Interindividual variability and parent of origin DNA methylation differences at specific human Alu elements." Human Molecular Genetics 14, no. 15 (2005): 2135–43. http://dx.doi.org/10.1093/hmg/ddi218.
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Gebert, Claudia, David Kunkel, Alexander Grinberg, and Karl Pfeifer. "H19 Imprinting Control Region Methylation Requires an Imprinted Environment Only in the Male Germ Line." Molecular and Cellular Biology 30, no. 5 (2009): 1108–15. http://dx.doi.org/10.1128/mcb.00575-09.
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ABSTRACT The 2.4-kb H19 imprinting control region (H19ICR) is required to establish parent-of-origin-specific epigenetic marks and expression patterns at the Igf2/H19 locus. H19ICR activity is regulated by DNA methylation. The ICR is methylated in sperm but not in oocytes, and this paternal chromosome-specific methylation is maintained throughout development. We recently showed that the H19ICR can work as an ICR even when inserted into the normally nonimprinted alpha fetoprotein locus. Paternal but not maternal copies of the ICR become methylated in somatic tissue. However, the ectopic ICR remains unmethylated in sperm. To extend these findings and investigate the mechanisms that lead to methylation of the H19ICR in the male germ line, we characterized novel mouse knock-in lines. Our data confirm that the 2.4-kb element is an autonomously acting ICR whose function is not dependent on germ line methylation. Ectopic ICRs become methylated in the male germ line, but the timing of methylation is influenced by the insertion site and by additional genetic information. Our results support the idea that DNA methylation is not the primary genomic imprint and that the H19ICR insertion is sufficient to transmit parent-of-origin-dependent DNA methylation patterns independent of its methylation status in sperm.
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Zhao, Guisen, Qingen Yang, Daixin Huang, et al. "Study on the application of parent-of-origin specific DNA methylation markers to forensic genetics." Forensic Science International 154, no. 2-3 (2005): 122–27. http://dx.doi.org/10.1016/j.forsciint.2004.09.123.
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Koetsier, P. A., and W. Doerfler. "Influence of Mouse-Strain-Specific Factors on Position-Dependent Transgene DNA Methylation Patterns." Acta geneticae medicae et gemellologiae: twin research 45, no. 1-2 (1996): 243–44. http://dx.doi.org/10.1017/s0001566000001380.
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In previous work from this laboratory, an inverse dependence was established for the adenovirus type 2 E2A late promoter between sequence-specific DNA methylation and promoter activity [1-5; for reviews see ref. 6, 7]. The effect of DNA methylation on promoter activity was also assessed in the transgenic mice, which were obtained from microinjections of unmethylated or in vitro HpaII-premethylated pAd2E2AL-CAT DNA [1] into F2 zygotes from B6D2F, (C57BL/6 × DBA/2) hybrid mice. In CAT assays carried out on organ extracts from the pAd2E2AL-CAT mice, the inverse relationship was confirmed [2].We studied the stability of the pAd2E2AL-CAT DNA methylation patterns in up to eight mouse generations and assessed the influence of the strain-specific genetic background. Three pAd2E2AL-CAT mouse lines were crossed with inbred DBA/2, C57BL/6 or B6D2F, mice. Parent-of-origin effects were controlled by exclusive hemizygous transgene transmission either via females or males. The founder animal of line 7-1 carried two groups of transgenes (A and B) on separate chromosomes. The transgene methylation patterns of the 7-1B transgenes and those of the lines 5-8 and 8-1 were stably transmitted.Southern blot hybridization experiments [8, 9] revealed that the 7-1A transgene methylation pattern was a cellular mosaic. In mixed-genetic-background offspring from 7-1A animals, 10% carried transgenes with HpaII-DNA methylation levels that were reduced from 40 to 10-15%. This finding suggested that in this background the factors that supported high methylation levels were dominant. When inbred DBA/2 mice were the mates, 40% of the siblings carried demethylated transgenes, whereas this ratio amounted to only 10% in C57BL/6 offspring (comparable to B6D2F1 crossings). Transgene methylation patterns were not detectably influenced by the parent-of-origin.
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Martin, C. Cristofre, and Ross McGowan. "Parent-of-origin specific effects on the methylation of a transgene in the zebrafish,Danio rerio." Developmental Genetics 17, no. 3 (1995): 233–39. http://dx.doi.org/10.1002/dvg.1020170308.
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Li, Li-Lan, Irene Yuk-yee Szeto, Bruce M. Cattanach, Fumitoshi Ishino, and M. Azim Surani. "Organization and Parent-of-Origin-Specific Methylation of Imprinted Peg3 Gene on Mouse Proximal Chromosome 7." Genomics 63, no. 3 (2000): 333–40. http://dx.doi.org/10.1006/geno.1999.6103.
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Szabó, Piroska E., Gerd P. Pfeifer, and Jeffrey R. Mann. "Parent-of-Origin-Specific Binding of Nuclear Hormone Receptor Complexes in the H19-Igf2 Imprinting Control Region." Molecular and Cellular Biology 24, no. 11 (2004): 4858–68. http://dx.doi.org/10.1128/mcb.24.11.4858-4868.2004.
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ABSTRACT Parent-of-origin-specific expression of the mouse insulin-like growth factor 2 gene (Igf2) and the closely linked H19 gene located on distal chromosome 7 is regulated by a 2.4-kb imprinting control region (ICR) located upstream of the H19 gene. In somatic cells, the maternally and paternally derived ICRs are hypo- and hypermethylated, respectively, with the former binding the insulator protein CCCTC-binding factor (CTCF) and acting to block access of enhancers to the Igf2 promoter. Here we report on a detailed in vivo footprinting analysis—using ligation-mediated PCR combined with in vivo dimethyl sulfate, DNase I, or UV treatment—of ICR sequences located outside of the CTCF binding domains. In mouse primary embryo fibroblasts carrying only maternal or paternal copies of distal chromosome 7, we have identified five prominent footprints specific to the maternal ICR. Each of the five footprinted areas contains at least two nuclear hormone receptor hexad binding sites arranged with irregular spacing. When combined with fibroblast nuclear extracts, these sequences interact with complexes containing retinoic X receptor alpha and estrogen receptor beta. More significantly, the footprint sequences bind nuclear hormone receptor complexes in male, but not female, germ cell extracts purified from fetuses at a developmental stage corresponding to the time of establishment of differential ICR methylation. These data are consistent with the possibility that nuclear hormone receptor complexes participate in the establishment of differential ICR methylation imprinting in the germ line.
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Sasaki, H., T. Hamada, T. Ueda, R. Seki, T. Higashinakagawa, and Y. Sakaki. "Inherited type of allelic methylation variations in a mouse chromosome region where an integrated transgene shows methylation imprinting." Development 111, no. 2 (1991): 573–81. http://dx.doi.org/10.1242/dev.111.2.573.
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It is still unclear whether or not parent-of-origin-dependent differential methylation observed in some transgenes reflects genomic imprinting of endogenous genes. We have characterized a transgene locus showing such methylation imprinting together with the corresponding native chromosome region. We show that only part of the transgene is affected by methylation imprinting and the methylation pattern is established before early prophase I during spermatogenesis. Interestingly, the native genomic region, which is mapped to the proximal chromosome 11, shows no evidence of methylation imprinting but displays heritable, strain-specific type of allelic methylation differences. The results demonstrate that transgenes do not necessarily reflect the methylation status of either the surrounding or corresponding chromosome region. In addition, inherited type of allelic methylation variations previously described in human may be widespread in mammals.
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Pun, F., C. Zhao, W. Lo, et al. "Imprinting in the schizophrenia candidate gene GABRB2." European Psychiatry 26, S2 (2011): 823. http://dx.doi.org/10.1016/s0924-9338(11)72528-7.
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Imprinting, characterized by unequal expression of the offspring's genes in a parent-of-origin dependent manner, has been functionally implicated in brain development and in psychiatric disorders. In this study, unambiguous distortion in paternal but not maternal transmission of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 (T/G) clearly indicated the presence of parent-of-origin effect (POE) in the GABAA receptor β2 subunit gene (GABRB2). ‘Flipping’ of allelic mRNA expression in heterozygotes of SNP rs2229944 (C/T) and the observed two-tiered distribution of mRNA expression levels in heterozygotes of the disease-associated SNP rs1816071 (G/A) furnished important support for the occurrence of imprinting at GABRB2. Imprinting in effect introduced heterozygotes from different parents-of-origin endowed with dissimilar mRNA expression capabilities. The deficit of upper-tiered expressions accounted for the lowered mRNA expression levels in the schizophrenic heterozygotes. This pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, allele-specific methylation was observed at the disease-associated SNPs rs6556547 and rs1816071. These findings raised the possibility that CpG methylation status of these sites could have an impact on the expression of GABRB2 and the risk of schizophrenia. Furthermore, the occurrence of imprinting and allele-specific methylation in the schizophrenia candidate gene GABRB2 was compatible with the epigenetic hypothesis for schizophrenia pathophysiology, thereby calling for the need to explore the role of epigenetic factors in mediating susceptibility to schizophrenia.
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Szpecht-Potocka, A., E. Obersztyn, M. Karwacki, E. Bocian, J. Bal, and T. Mazurczak. "Molecular and Clinical Studies of Polish Patients with Prader-Willi Syndrome." Acta geneticae medicae et gemellologiae: twin research 45, no. 1-2 (1996): 273–76. http://dx.doi.org/10.1017/s0001566000001446.
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AbstractA group of 30 patients clinically described as having the Prader-Willi Syndrome (PWS) were studied using microsatellites from 15q11-13 and methylation analysis with probe PW71B (D15S63). The patients were categorized according to clinical symptoms. 80% of all patients were informative using molecular and cytogenetic methods. Among 8 patients with an atypical PWS phenotype, 2 showed uniparental disomy, and 2 had a mosaic deletion for 15q. The last 4 atypical and 2 typical patients had neither molecular defects confirmed by microsatellite analysis nor a parent-of-origin-specific methylation pattern for PWS. Our results confirm that methylation pattern analysis provides an additional and alternative microsatellite analysis to diagnose PWS.
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Pandey, Radha Raman, Michele Ceribelli, Prim B. Singh, Johan Ericsson, Roberto Mantovani, and Chandrasekhar Kanduri. "NF-Y Regulates the Antisense Promoter, Bidirectional Silencing, and Differential Epigenetic Marks of theKcnq1Imprinting Control Region." Journal of Biological Chemistry 279, no. 50 (2004): 52685–93. http://dx.doi.org/10.1074/jbc.m408084200.
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Antisense transcription has been shown to be one of the hierarchies that control gene expression in eukaryotes. Recently, we have documented that the mouseKcnq1imprinting control region (ICR) harbors bidirectional silencing property, and this feature is linked to an antisense RNA,Kcnq1ot1. In this investigation, using genomic footprinting, we have identified three NF-Y transcription factor binding sites appearing in a methylation-sensitive manner in theKcnq1ot1promoter. By employing a dominant negative mutant to the NF-Y transcription factor, we have shown that the NF-Y transcription factor positively regulates antisense transcription. Selective mutation of the conserved nucleotides in the NF-Y binding sites resulted in the loss of antisense transcription. The loss of antisense transcription from theKcnq1ot1promoter coincides with an enrichment in the levels of deacetylation and methylation at the lysine 9 residue of histone H3 and DNA methylation at the CpG residues, implying a crucial role for the NF-Y transcription factor in organizing the parent of origin-specific chromatin conformation in theKcnq1ICR. Parallel to the loss of antisense transcription, the loss of silencing of the flanking reporter genes was observed, suggesting that NF-Y-mediatedKcnq1ot1transcription is critical in the bidirectional silencing process of theKcnq1ICR. These data highlight the NF-Y transcription factor as a crucial regulator of antisense promoter-mediated bidirectional silencing and the parent of origin-specific epigenetic marks at theKcnq1ICR. More importantly, for the first time, we document that NF-Y is involved in maintaining the antisense promoter activity against strong silencing conditions.
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Kubota, T., S. Aradhya, M. Macha, et al. "Analysis of parent of origin specific DNA methylation at SNRPN and PW71 in tissues: implication for prenatal diagnosis." Journal of Medical Genetics 33, no. 12 (1996): 1011–14. http://dx.doi.org/10.1136/jmg.33.12.1011.
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Bongiorni, Silvia, Orietta Cintio, and Giorgio Prantera. "The Relationship Between DNA Methylation and Chromosome Imprinting in the Coccid Planococcus citri." Genetics 151, no. 4 (1999): 1471–78. http://dx.doi.org/10.1093/genetics/151.4.1471.
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Abstract The phenomenon of chromosome, or genomic, imprinting indicates the relevance of parental origin in determining functional differences between alleles, homologous chromosomes, or haploid sets. In mealybug males (Homoptera, Coccoidea), the haploid set of paternal origin undergoes heterochromatization at midcleavage and remains so in most of the tissues. This different behavior of the two haploid sets, which depends on their parental origin, represents one of the most striking examples of chromosome imprinting. In mammals, DNA methylation has been postulated as a possible molecular mechanism to differentially imprint DNA sequences during spermatogenesis or oogenesis. In the present article we addressed the role of DNA methylation in the imprinting of whole haploid sets as it occurs in Coccids. We investigated the DNA methylation patterns at both the molecular and chromosomal level in the mealybug Planococcus citri. We found that in both males and females the paternally derived haploid set is hypomethylated with respect to the maternally derived one. Therefore, in males, it is the paternally derived hypomethylated haploid set that is heterochromatized. Our data suggest that the two haploid sets are imprinted by parent-of-origin-specific DNA methylation with no correlation with the known gene-silencing properties of this base modification.
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Rodrigues, Jessica A., Ping-Hung Hsieh, Deling Ruan, et al. "Divergence among rice cultivars reveals roles for transposition and epimutation in ongoing evolution of genomic imprinting." Proceedings of the National Academy of Sciences 118, no. 29 (2021): e2104445118. http://dx.doi.org/10.1073/pnas.2104445118.
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Parent-of-origin–dependent gene expression in mammals and flowering plants results from differing chromatin imprints (genomic imprinting) between maternally and paternally inherited alleles. Imprinted gene expression in the endosperm of seeds is associated with localized hypomethylation of maternally but not paternally inherited DNA, with certain small RNAs also displaying parent-of-origin–specific expression. To understand the evolution of imprinting mechanisms in Oryza sativa (rice), we analyzed imprinting divergence among four cultivars that span both japonica and indica subspecies: Nipponbare, Kitaake, 93-11, and IR64. Most imprinted genes are imprinted across cultivars and enriched for functions in chromatin and transcriptional regulation, development, and signaling. However, 4 to 11% of imprinted genes display divergent imprinting. Analyses of DNA methylation and small RNAs revealed that endosperm-specific 24-nt small RNA–producing loci show weak RNA-directed DNA methylation, frequently overlap genes, and are imprinted four times more often than genes. However, imprinting divergence most often correlated with local DNA methylation epimutations (9 of 17 assessable loci), which were largely stable within subspecies. Small insertion/deletion events and transposable element insertions accompanied 4 of the 9 locally epimutated loci and associated with imprinting divergence at another 4 of the remaining 8 loci. Correlating epigenetic and genetic variation occurred at key regulatory regions—the promoter and transcription start site of maternally biased genes, and the promoter and gene body of paternally biased genes. Our results reinforce models for the role of maternal-specific DNA hypomethylation in imprinting of both maternally and paternally biased genes, and highlight the role of transposition and epimutation in rice imprinting evolution.
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Procter, Melinda, Lan-Szu Chou, Wei Tang, Mohamed Jama, and Rong Mao. "Molecular Diagnosis of Prader–Willi and Angelman Syndromes by Methylation-Specific Melting Analysis and Methylation-Specific Multiplex Ligation-Dependent Probe Amplification." Clinical Chemistry 52, no. 7 (2006): 1276–83. http://dx.doi.org/10.1373/clinchem.2006.067603.
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Abstract Background: Approximately 99% of Prader–Willi syndrome (PWS) and 80% of Angelman syndrome (AS) cases have deletions at a common region in chromosome 15q11.2-q13, uniparental disomy for chromosome 15 (UPD15), or imprinting center defects affecting gene expression in this region. The resulting clinical phenotype (PWS or AS) in each class of genomic abnormalities depends on the parent of origin. Both disorders are characterized at the molecular level by abnormal methylation of imprinted regions at 15q11.2-q13. Other rare chromosome 15 rearrangements and a few smaller atypical deletions associated with abnormal methylation patterns also have symptoms overlapping with either PWS or AS. Methods: We designed a methylation-specific melting analysis (MS-MA) method for a rapid screening of PWS/AS and evaluated methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for diagnosis of PWS/AS associated with deletions, UPD15, or rare duplications. Forty-nine previously genotyped samples were tested by MS-MA. We also tested 26 MS-MA genotyped samples and 1 additional sample with rare duplication of chromosome region 15q11-q12. Results: PWS/AS genotyping results obtained by MS-MA and by MS-MLPA were fully concordant. In addition, MS-MLPA was superior in detecting deletions/rare duplications, possible UPD15, or imprinting center defects, which were usually determined by a laborious fluorescence in situ hybridization method or by chromosomal segregation analysis for the parental-origin using short-tandem repeat makers. Conclusions: MS-MA appears to be an efficient primary method to diagnose PWS/AS, and use of the quantitative MS-MLPA method provides detailed information about deletions, rare duplications, and possibly UPD.
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Weaver, Jamie R., Garnik Sarkisian, Christopher Krapp, Jesse Mager, Mellissa R. W. Mann, and Marisa S. Bartolomei. "Domain-Specific Response of Imprinted Genes to Reduced DNMT1." Molecular and Cellular Biology 30, no. 16 (2010): 3916–28. http://dx.doi.org/10.1128/mcb.01278-09.
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ABSTRACT Imprinted genes are expressed in a monoallelic, parent-of-origin-specific manner. Clusters of imprinted genes are regulated by imprinting control regions (ICRs) characterized by DNA methylation of one allele. This methylation is critical for imprinting; a reduction in the DNA methyltransferase DNMT1 causes a widespread loss of imprinting. To better understand the role of DNA methylation in the regulation of imprinting, we characterized the effects of Dnmt1 mutations on the expression of a panel of imprinted genes in the embryo and placenta. We found striking differences among imprinted domains. The Igf2 and Peg3 domains showed imprinting perturbations with both null and partial loss-of-function mutations, and both domains had pairs of coordinately regulated genes with opposite responses to loss of DNMT1 function, suggesting these domains employ similar regulatory mechanisms. Genes in the Kcnq1 domain were less sensitive to the absence of DNMT1. Cdkn1c exhibited imprinting perturbations only in null mutants, while Kcnq1 and Ascl2 were largely unaffected by a loss of DNMT1 function. These results emphasize the critical role for DNA methylation in imprinting and reveal the different ways it controls gene expression.
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Trasler, Jacquetta M. "Gamete imprinting: setting epigenetic patterns for the next generation." Reproduction, Fertility and Development 18, no. 2 (2006): 63. http://dx.doi.org/10.1071/rd05118.
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The acquisition of genomic DNA methylation patterns, including those important for development, begins in the germ line. In particular, imprinted genes are differentially marked in the developing male and female germ cells to ensure parent-of-origin-specific expression in the offspring. Abnormalities in imprints are associated with perturbations in growth, placental function, neurobehavioural processes and carcinogenesis. Based, for the most part, on data from the well-characterised mouse model, the present review will describe recent studies on the timing and mechanisms underlying the acquisition and maintenance of DNA methylation patterns in gametes and early embryos, as well as the consequences of altering these patterns.
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Ahn, Jinsoo, In-Sul Hwang, Mi-Ryung Park, Seongsoo Hwang, and Kichoon Lee. "Genomic Imprinting at the Porcine DIRAS3 Locus." Animals 11, no. 5 (2021): 1315. http://dx.doi.org/10.3390/ani11051315.
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The epigenetic mechanisms underlying genomic imprinting include DNA methylation and monoallelic expression of genes in close proximity. Although genes imprinted in humans and mice have been widely characterized, there is a lack of detailed and comprehensive studies in livestock species including pigs. The purpose of this study was to investigate a detailed methylation status and parent-of-origin-specific gene expression within the genomic region containing an underexamined porcine DIRAS3 locus. Through whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of porcine parthenogenetic embryos and analyses of public RNA-seq data from adult pigs, DNA methylation and monoallelic expression pattern were investigated. As a result, maternal hypermethylation at the DIRAS3 locus and hypothalamus-specific and monoallelic expression of the DIRAS3 gene were found in pigs. In conclusion, the findings from this study suggest that the presence of maternal hypermethylation, or imprints, might be maintained and related to monoallelic expression of DIRAS3 during pig development.
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Kanduri, Chandrasekhar, Vinod Pant, Dmitri Loukinov, et al. "Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive." Current Biology 10, no. 14 (2000): 853–56. http://dx.doi.org/10.1016/s0960-9822(00)00597-2.
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Ogunwuyi, Oluwaseun, Ankur Upadhyay, Simeon K. Adesina, et al. "Genetic Imprinting: Comparative Analysis Between Plants and Mammals." Plant Tissue Culture and Biotechnology 26, no. 2 (2016): 267–84. http://dx.doi.org/10.3329/ptcb.v26i2.30576.
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Genetic imprinting: the parent of origin?specific biased expression of alleles is an important type of epigenetic gene regulation in flowering plants and mammals. All imprinted genes show either maternal ? or paternal?specific mono?allelic expression. Considering that plants and mammals shared a common ancestor more than one billion years ago, significant overlap and potentially equally significant differences in the genomic imprinting mechanisms in these two taxa are emerging. In plants, the imprinted genes are primarily imprinted in the ephemeral endosperm tissues of the seeds which do not contribute any genome to future generations, while in mammals, the imprinted genes are located in embryo, placenta, and the adult body. Though both kingdoms silence imprinted genes using DNA methylation, imprinted alleles in mammals are targeted for silencing while in plants preexisting methylation is specifically removed from the allele destined to be active in maternally expressed genes in the endosperm. It is now accepted that imprinting evolved in both taxa due to competition between parental genomes over resource allocation to offspring. Moreover, the distinct life cycle stages between the taxa may account for the different strategies used by plants and mammals to regulate parent?specific gene expression. The elucidation of the genetic basis and molecular mechanisms responsible for genetic imprinting have provided answers to various crucial questions arising in biological sciencesPlant Tissue Cult. & Biotech. 26(2): 267-284, 2016 (December)
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Du, Miru, Ming Luo, Ruofang Zhang, E. Jean Finnegan, and Anna M. G. Koltunow. "Imprinting in rice: the role of DNA and histone methylation in modulating parent-of-origin specific expression and determining transcript start sites." Plant Journal 79, no. 2 (2014): 232–42. http://dx.doi.org/10.1111/tpj.12553.
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Swales, A. K. E., and N. Spears. "Genomic imprinting and reproduction." Reproduction 130, no. 4 (2005): 389–99. http://dx.doi.org/10.1530/rep.1.00395.
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Genomic imprinting is the parent-of-origin specific gene expression which is a vital mechanism through both development and adult life. One of the key elements of the imprinting mechanism is DNA methylation, controlled by DNA methyltransferase enzymes. Germ cells undergo reprogramming to ensure that sex-specific genomic imprinting is initiated, thus allowing normal embryo development to progress after fertilisation. In some cases, errors in genomic imprinting are embryo lethal while in others they lead to developmental disorders and disease. Recent studies have suggested a link between the use of assisted reproductive techniques and an increase in normally rare imprinting disorders. A greater understanding of the mechanisms of genomic imprinting and the factors that influence them are important in assessing the safety of these techniques.
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Freschi, Andrea, Rosita Del Prete, Laura Pignata, et al. "The number of the CTCF binding sites of the H19/IGF2:IG-DMR correlates with DNA methylation and expression imprinting in a humanized mouse model." Human Molecular Genetics 30, no. 16 (2021): 1509–20. http://dx.doi.org/10.1093/hmg/ddab132.
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Abstract The reciprocal parent of origin-specific expression of H19 and IGF2 is controlled by the H19/IGF2:IG-DMR (IC1), whose maternal allele is unmethylated and acts as a CTCF-dependent insulator. In humans, internal IC1 deletions are associated with Beckwith–Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS), depending on their parental origin. These genetic mutations result in aberrant DNA methylation, deregulation of IGF2/H19 and disease with incomplete penetrance. However, the mechanism linking the microdeletions to altered molecular and clinical phenotypes remains unclear. To address this issue, we have previously generated and characterized two knock-in mouse lines with the human wild-type (hIC1wt) or mutant (hIC1∆2.2) IC1 allele replacing the endogenous mouse IC1 (mIC1). Here, we report an additional knock-in line carrying a mutant hIC1 allele with an internal 1.8 kb deletion (hIC1∆1.8). The phenotype of these mice is different from that of the hIC1∆2.2-carrying mice, partially resembling hIC1wt animals. Indeed, proper H19 and Igf2 imprinting and normal growth phenotype were evident in the mice with maternal transmission of hIC1Δ1.8, while low DNA methylation and non-viable phenotype characterize its paternal transmission. In contrast to hIC1wt, E15.5 embryos that paternally inherit hIC1Δ1.8 displayed variegated hIC1 methylation. In addition, increased Igf2 expression, correlating with increased body weight, was found in one third of these mice. Chromatin immunoprecipitation experiments in mouse embryonic stem cells carrying the three different hIC1 alleles demonstrate that the number of CTCF target sites influences its binding to hIC1, indicating that in the mouse, CTCF binding is key to determining hIC1 methylation and Igf2 expression.
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Seitz, Hervé, Hélène Royo, Shau-Ping Lin, Neil Youngson, Anne C. Ferguson-Smith, and Jérôme Cavaillé. "Imprinted small RNA genes." Biological Chemistry 385, no. 10 (2004): 905–11. http://dx.doi.org/10.1515/bc.2004.118.
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Abstract Genomic imprinting is an epigenetic phenomenon that results in differential expression of both alleles, depending on their parent of origin. We have recently identified many imprinted small non-coding RNA genes belonging to the C/D RNA and microRNA gene families, both of which are usually known to play key roles in post-transcriptional metabolism of specific genes (e.g. C/D RNAs guide ribose methylation of target RNAs while microRNAs elicit either translational repression or RNA interference). Although the functional and evolutionary significance of this association between C/D RNA genes, microRNA genes and genomic imprinting is still highly elusive, these observations provide a framework for further analysis of the potential role of small non-coding RNAs in epigenetic control.
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Robles-Matos, Nicole, Tre Artis, Rebecca A. Simmons, and Marisa S. Bartolomei. "Environmental Exposure to Endocrine Disrupting Chemicals Influences Genomic Imprinting, Growth, and Metabolism." Genes 12, no. 8 (2021): 1153. http://dx.doi.org/10.3390/genes12081153.
Full textAbstract:
Genomic imprinting is an epigenetic mechanism that results in monoallelic, parent-of-origin-specific expression of a small number of genes. Imprinted genes play a crucial role in mammalian development as their dysregulation result in an increased risk of human diseases. DNA methylation, which undergoes dynamic changes early in development, is one of the epigenetic marks regulating imprinted gene expression patterns during early development. Thus, environmental insults, including endocrine disrupting chemicals during critical periods of fetal development, can alter DNA methylation patterns, leading to inappropriate developmental gene expression and disease risk. Here, we summarize the current literature on the impacts of in utero exposure to endocrine disrupting chemicals on genomic imprinting and metabolism in humans and rodents. We evaluate how early-life environmental exposures are a potential risk factor for adult metabolic diseases. We also introduce our mouse model of phthalate exposure. Finally, we describe the potential of genomic imprinting to serve as an environmental sensor during early development and as a novel biomarker for postnatal health outcomes.
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Hiendleder, S., D. Bebbere, S. Bauersachs, et al. "106 GENOMIC IMPRINTING OF IGF2R IN TISSUES OF BOVINE FETUSES GENERATED BY ARTIFICIAL INSEMINATION OR IN VITRO FERTILIZATION." Reproduction, Fertility and Development 17, no. 2 (2005): 204. http://dx.doi.org/10.1071/rdv17n2ab106.
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The insulin-like growth factor 2 receptor gene (IGF2R) is involved in fetal growth regulation. A study in sheep associated fetal overgrowth after in vitro embryo culture with abnormal DNA methylation and expression of IGF2R (Young et al. 2001 Nat. Genet. 27, 153–154). This suggested that abnormal IGF2R imprinting is a major cause of fetal overgrowth. To test this hypothesis in bovine fetuses, we developed a microsatellite marker for IGF2R from cDNA sequence data and screened 45 Day-80 fetuses generated in vivo, by artificial insemination (AI), or in vitro, by in vitro fertilization (IVF) procedures, for parent-of-origin-specific gene expression. A total of 17 fetuses were heterozygous, but available parental DNA samples showed that only 12 (8 AI, 4 IVF) allowed unambiguous discrimination of parental alleles. Parent-of-origin-specific allelic expression patterns indicated that bovine IGF2R was expressed predominantly from the maternal allele and thus imprinted in fetal heart, kidney, liver, lung, muscle, and cotyledon tissue. However, the relative amount of expression from the paternal allele was tissue-specific and ranged from 6.4 ± 0.8% in skeletal muscle up to 27.4 ± 0.9% in cotyledon (SPSS or 11.5, ANOVA, P < 0.001). Tissues that originated from the same germ layer showed similar allelic expression ratios whereas significantly different expression ratios (P < 0.05) were observed between tissues originating from different germ layers. Contrary to expectations from sheep data, there was no evidence for gross abnormalities in IGF2R imprinting in tissues from overgrown (n = 2) or normal sized (n = 2) IVF fetuses. However, relative paternal expression levels in several tissues showed significant relationships (P < 0.05–0.001) with growth parameters and pointed to subtle changes in paternal IGF2R expression in overgrown IVF fetuses. We thank W. Scholz and M. Weppert for excellent technical assistance.
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Zhu, Haifeng, Wenxiang Xie, Dachao Xu, et al. "DNA demethylase ROS1 negatively regulates the imprinting of DOGL4 and seed dormancy in Arabidopsis thaliana." Proceedings of the National Academy of Sciences 115, no. 42 (2018): E9962—E9970. http://dx.doi.org/10.1073/pnas.1812847115.
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Genomic imprinting is a form of epigenetic regulation resulting in differential gene expression that reflects the parent of origin. In plants, imprinted gene expression predominantly occurs in the seed endosperm. Maternal-specific DNA demethylation by the DNA demethylase DME frequently underlies genomic imprinting in endosperm. Whether other more ubiquitously expressed DNA demethylases regulate imprinting is unknown. Here, we found that the DNA demethylase ROS1 regulates the imprinting of DOGL4. DOGL4 is expressed from the maternal allele in endosperm and displays preferential methylation and suppression of the paternal allele. We found that ROS1 negatively regulates imprinting by demethylating the paternal allele, preventing its hypermethylation and complete silencing. Furthermore, we found that DOGL4 negatively affects seed dormancy and response to the phytohormone abscisic acid and that ROS1 controls these processes by regulating DOGL4. Our results reveal roles for ROS1 in mitigating imprinted gene expression and regulating seed dormancy.
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Pina-Neto, João M. de, Victor Evangelista F. Ferraz, Greice Andreotti de Molfetta, Jess Buxton, Sarah Richards, and Sue Malcolm. "Clinical-neurologic, cytogenetic and molecular aspects of the Prader-Willi and Angelman Syndromes." Arquivos de Neuro-Psiquiatria 55, no. 2 (1997): 199–208. http://dx.doi.org/10.1590/s0004-282x1997000200006.
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The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are human neurogenetic disorders involving the imprinting mechanism, at the 15q11-13 chromosome region. The predominant genetic defects in PW are 15q 11-13 deletions of paternal origin and maternal chromosome 15 uniparental disomy. In contrast, maternal deletions and paternal chromosome 15 uniparental disomy are associated with a different neurogenetic disorder, the AS. In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q 11-13 loci. We studied 5 patients suspect of PWS and 4 patients suspect of AS who were referred to the Medical Genetics Unit at the University Hospital of Medical School from Ribeirão Preto. Our objective was to establish the correct clinical and etiological diagnosis in these cases. We used conventional cytogenetics, methylation analysis with the probe KB 17 (CpG island of the SNRPN gene) by Southern blotting after digestion with the Xba I and Not I restriction enzymes. We studied in patients and their parents the segregation of the (CA)n repeats polymorphisms by PCR, using the primers 196 and IR4-3R. All the patients had normal conventional cytogenetical analysis. We confirmed 3 cases of PWS: one by de novo deletion, one by maternal chromosome 15 uniparental disomy and one case with no defined cause determined by the used primers. We confirmed 2 cases of AS, caused by de novo deletion at the 15q 11-13 region, and one case with normal molecular analysis but with strong clinical characteristics.
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Hur, Stella K., Andrea Freschi, Folami Ideraabdullah, et al. "Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver–Russell syndrome phenotypes." Proceedings of the National Academy of Sciences 113, no. 39 (2016): 10938–43. http://dx.doi.org/10.1073/pnas.1603066113.
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Genomic imprinting affects a subset of genes in mammals, such that they are expressed in a monoallelic, parent-of-origin–specific manner. These genes are regulated by imprinting control regions (ICRs), cis-regulatory elements that exhibit allele-specific differential DNA methylation. Although genomic imprinting is conserved in mammals, ICRs are genetically divergent across species. This raises the fundamental question of whether the ICR plays a species-specific role in regulating imprinting at a given locus. We addressed this question at the H19/insulin-like growth factor 2 (Igf2) imprinted locus, the misregulation of which is associated with the human imprinting disorders Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS). We generated a knock-in mouse in which the endogenous H19/Igf2 ICR (mIC1) is replaced by the orthologous human ICR (hIC1) sequence, designated H19hIC1. We show that hIC1 can functionally replace mIC1 on the maternal allele. In contrast, paternally transmitted hIC1 leads to growth restriction, abnormal hIC1 methylation, and loss of H19 and Igf2 imprinted expression. Imprint establishment at hIC1 is impaired in the male germ line, which is associated with an abnormal composition of histone posttranslational modifications compared with mIC1. Overall, this study reveals evolutionarily divergent paternal imprinting at IC1 between mice and humans. The conserved maternal imprinting mechanism and function at IC1 demonstrates the possibility of modeling maternal transmission of hIC1 mutations associated with BWS in mice. In addition, we propose that further analyses in the paternal knock-in H19+/hIC1 mice will elucidate the molecular mechanisms that may underlie SRS.
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Market, Brenna A., Liyue Zhang, Lauren S. Magri, Michael C. Golding, and Mellissa RW Mann. "INVESTIGATING THE MOLECULAR AND DEVELOPMENTAL EFFECTS OF VARIOUS CULTURE REGIMES IN A MOUSE MODEL SYSTEM." Clinical & Investigative Medicine 31, no. 4 (2008): 16. http://dx.doi.org/10.25011/cim.v31i4.4814.
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Background/Purpose: Genomic imprinting is a specialized transcriptional mechanism that results in the unequal expression of alleles based on their parent-of-origin [1]. Many imprinted genes are critical for proper embryonic and fetaldevelopment [2] and disruption of genomic imprinting are associated with many development disorders [3]. Recently, increased frequencies of imprinting disorders have been correlated with the use of assisted reproductive technologies (ARTs)[2]. Rigorous and thorough testing of ARTs is required to determine their influence on genomic imprinting and development. I hypothesize that imprinting maintenance mechanisms are disrupted during early mouse development by the environmental insult of culture media used in human ARTs, and that loss of imprinting correlates with delayed embryonic development. Methods: The specific aims of my project are to develop a method to evaluate the methylation and expression patterns of 4 known imprinted genes in individual blastocysts. Results: We have successfully developed a novel method to evaluate both imprinted methylation and expression from a single mouse blastocyst. This method has been tested and results compared to methods used to evaluate imprinted methylation and expression separately; we have determined that results obtained with a combined protocol are equivalent to either alone. I will use this method to evaluate relationships between development rates in culture andgenomic imprinting, as well as the effects of various culture media used formouse and human embryo culture on genomic imprinting. Conclusion: This analysis allow for a more comprehensive study ofthe effects of environmental insult on genomic imprinting and preimplantation embryo development. References: 1. Reik W, Walter J. Genomic imprinting:parental influence on the genome. Nat Rev Genet 2001;2:21-32. 2. Rodenhiser D, Mann M. Epigenetics andhuman disease: translating basic biology into clinical applications. CMAJ. 2006;174:341-8. 3.Paoloni-Giacobino A. Epigenetics in reproductive medicine. Pediatr Res 2007;61:51R-57R.
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Thakur, Noopur, Vijay Kumar Tiwari, Helene Thomassin, et al. "An Antisense RNA Regulates the Bidirectional Silencing Property of the Kcnq1 Imprinting Control Region." Molecular and Cellular Biology 24, no. 18 (2004): 7855–62. http://dx.doi.org/10.1128/mcb.24.18.7855-7862.2004.
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ABSTRACT The Kcnq1 imprinting control region (ICR) located in intron 10 of the Kcnq1 gene is unmethylated on the paternal chromosome and methylated on the maternal chromosome and has been implicated in the manifestation of parent-of-origin-specific expression of six neighboring genes. The unmethylated Kcnq1 ICR harbors bidirectional silencer activity and drives expression of an antisense RNA, Kcnq1ot1, which overlaps the Kcnq1 coding region. To elucidate whether the Kcnq1ot1 RNA plays a role in the bidirectional silencing activity of the Kcnq1 ICR, we have characterized factor binding sites by genomic footprinting and tested the functional consequence of various deletions of these binding sites in an episome-based system. Deletion of the elements necessary for Kcnq1ot1 promoter function resulted in the loss of silencing activity. Furthermore, interruption of Kcnq1ot1 RNA production by the insertion of a polyadenylation sequence downstream of the promoter also caused a loss of both silencing activity and methylation spreading. Thus, the antisense RNA plays a key role in the silencing function of the ICR. Double-stranded RNA (dsRNA)-mediated RNA interference is unlikely to be involved, as the ICR is active irrespective of the simultaneous production of dsRNA from the genes it silences.
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Kaneda, M., S. Watanabe, S. Akagi, et al. "40 VARIOUS DNA METHYLATION LEVELS OF IMPRINTED GENES IN CLONED COWS FROM THE SAME DONOR CELLS." Reproduction, Fertility and Development 23, no. 1 (2011): 126. http://dx.doi.org/10.1071/rdv23n1ab40.
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Somatic cell nuclear transferred (SCNT) animals are genetically identical to the donors; however, because of epigenetic abnormalities caused by incomplete reprogramming during nuclear transfer, the efficiency of SCNT is still very low. Monozygotic twins are also genetically identical, but it is reported that their epigenetic patterns on the genome, the so-called epigenome, are different. The epigenome is easily influenced by aging, environmental changes and nutrients, therefore these effects can be predicted by comparing epigenetic differences between genetically identical animals. Here we analysed DNA methylation levels of imprinted genes, which express in a parent-of-origin specific manner, in various tissues of cloned cows derived from the same donor cells. Imprinted gene expression is controlled by DNA methylation and other epigenetic modifications and abnormal expression/methylation patterns of imprinted genes have been observed in cloned animals. These alterations also occur during in vitro development of preimplantation embryos, which suggests that imprinted genes are easily influenced by environmental changes. Therefore, we chose H19 and PEG3 imprinted genes for the analysis to determine the epigenetic differences between individual cloned cows derived from the same donor cells. From 5 cloned and 5 non-cloned cows, we isolated DNA from 8 tissues (heart, lung, liver, kidney, spleen, intestine, muscle, and spinal cord) and analysed DNA methylation levels by bisulfite sequencing method. Briefly, genomic DNA was isolated by QIAGEN DNeasy Blood & Tissue Kit and bisulfite converted by QIAGEN EpiTect Bisulfite Kits (Qiagen, Valencia, CA). After amplification, the PCR products were cloned into TA vector and at least 10 clones were sequenced in each gene/sample. In every tissue analysed, the methylation levels largely differ among tissues and individuals. On average, the paternally imprinted gene H19 was 9.4 to 47.9% methylated (average 27.6 ± 10.3%) in clones and 0.5 to 69.8% methylated (average 29.0 ± 16.8%) in non-clones. The maternally imprinted gene PEG3 was 18.8 to 82.2% methylated (average 43.5 ± 15.8%) in clones and 8.0 to 98.7% (average 48.2 ± 18.8%) in non-clones. Even though there were large variations in DNA methylation levels, the variability tends to be low in clones compared to non-clones. More specifically, the variabilities of H19 methylation levels in spleen and intestine were significantly lower in clones than those in non-clones (32.3 ± 5.4% v. 27.0 ± 19.0% and 25.1 ± 4.2% v. 45.1 ± 14.3%, respectively, F-test; P < 0.05). These results suggest for the first time that epigenetic patterns in some tissues of both clones and non-clones are influenced by genetic background; however, mostly they are varied depending on non-genetic factors.
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Bressan, F. F., J. Therrien, F. Filion, F. Perecin, L. C. Smith, and F. V. Meirelles. "331 ABNORMAL DNA METHYLATION PATTERNS AND ALLELE-SPECIFIC EXPRESSION OF IMPRINTED GENES IN BOVINE-INDUCED PLURIPOTENT STEM CELLS." Reproduction, Fertility and Development 27, no. 1 (2015): 254. http://dx.doi.org/10.1071/rdv27n1ab331.
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Pluripotency reacquisition of somatic cells has been achieved through nuclear transfer (NT) to oocytes and, more recently, through induction with pluripotency-related factors (iPS cells). However, the epigenetic reprogramming process that enables the derivation of both NT-derived cloned animals and iPS cells is usually incomplete, leading to unhealthy offspring and poorly reprogrammed iPS cell lines. These unfavourable outcomes result in part from abnormal genome DNA methylation that leads to aberrant gene expression patterns. For instance, differentially methylated regions (DMR) and monoalleleic expression of imprinted genes, essential for normal cellular commitment and early development, are thought to be severely disturbed by reprogramming techniques. Indeed, H19 and SNRPN, imprinted genes, were disturbed in bovine NT-derived embryos and fetuses. Herein we investigated whether the DMR and parent-of-origin expression of the imprinted genes H19 and SNRPN are also perturbed in iPS lines. To analyse the DMR methylation patterns and allelic expression of H19 and SNRPN using parental-specific polymorphisms, we derived multiple clones of bovine iPS (biPS) cells from an interspecies (Bos indicus × Bos taurus) fetal fibroblast (bFF) using transduction with a policystronic lentivirus containing mouse Oct4, Sox2 c-Myc, and Klf-4 transcription factors. The DNA methylation patterns were evaluated by bisulfite sequencing and allelic expression by designing allele-specific PCR probes. We also quantified transcript expression by RT-PCR of H19, IGF2, SNRPN, OCT4, and NANOG by normalization with 3 housekeeping genes (GAPDH, NAT1, and ACTB). The biPS lines were characterised by a high nuclear : cytoplasmic ratio, dome-shaped colonies, positive AP activity, embryoid body formation, in vitro and in vivo (teratoma) formation, and expression of pluripotency-related genes. Compared to the bFF cells, methylation analyses of H19 showed partial hypomethylation of the paternal DMR on 1 iPS cell line and partial demethylation of the CTCF-binding region in the DMR of 2 other biPS lines, indicating abnormal demethylation of 3 out of the 4 biPS lines analysed. Methylation analyses of SNRPN revealed a partial hypomethylation in the maternal DMR and partial hypermethylation of the paternal DMR in 2 iPS lines. Gene expression analyses revealed the biallelic expression of H19 and decreased global expression of both H19 and IGF2, as well as the exclusively monoallelic paternal expression and significant increase in global expression of SNRPN. Interestingly, although OCT4 was substantially overexpressed in biPS lines, we identified a hypermethylation of the CG-rich region of the OCT4 exon 1. Endogenous NANOG expression was observed in 2 biPS clones. We conclude that imprinting errors are observed in biPS clones, suggesting that these epigenetic anomalies are related to the reprogramming process and could be directly responsible for the variable phenotypes and low success rates of both cloning and iPS derivation procedures.Financial support was from NSERC, FAPESP (13/13686-8, 11/08376-4, 57877-3/2008, 08.135-2/2013), CNPq (573754/2008-0, 482163/2013-5).
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Lopez, S. Jesse, Benjamin I. Laufer, Ulrika Beitnere, et al. "Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways." Human Molecular Genetics 28, no. 22 (2019): 3842–52. http://dx.doi.org/10.1093/hmg/ddz221.
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Abstract Ubiquitin E3 ligase 3A (UBE3A) encodes an E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome (AS). Previous studies of UBE3A function have not examined full Ube3a deletion in mouse, the complexity of imprinted gene networks in brain nor the molecular basis of systems-level cognitive dysfunctions in AS. We therefore utilized a systems biology approach to elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9-engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, compared to wild-type littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype and time (P2 and P9) was investigated through transcriptome (RNA sequencing of cortex and hypothalamus) and methylome (whole-genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring enriched in postnatal developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment and splicing. Furthermore, we showed that loss of the paternal Ube3a antisense transcript resulted in both unique and overlapping dysregulated gene pathways with maternal loss, predominantly at the level of differential methylation. Together, these results provide a holistic examination of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.
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Nicholls, R. D., M. T. C. Jong, C. C. Glenn, et al. "Multiple Imprinted Genes Associated with Prader-Willi Syndrome and Location of an Imprinting Control Element." Acta geneticae medicae et gemellologiae: twin research 45, no. 1-2 (1996): 87–89. http://dx.doi.org/10.1017/s000156600000115x.
Full textAbstract:
Our studies aim to identify the mechanisms and genes involved in genomic imprinting in mammalian development and human disease. Imprinting refers to an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. This imprint is reset at each generation, depending on the sex of the parental gametogenesis. Prader-Willi (PWS) and Angelman (AS) syndromes are excellent models for the study of genomic imprinting in humans, since these distinct neurobehavioural disorders are both associated with genetic abnormalities (large deletions, uniparental disomy, and imprinting mutations) of inheritance in chromosome 15q11-q13, dependent on the parental origin (reviewed in ref. 1). Some AS patients have biparental inheritance, consistent with a single imprinted gene (active on the maternal chromosome), whereas similar PWS patients are not found suggesting that at least two imprinted genes (active on the paternal allele) may be necessary for classical PWS. We have previously shown that the small ribonucleoprotein associated protein SmN gene (SNRPN), located in the PWS critical region [2], is only expressed from the paternal allele and is differentially methylated on parental alleles [3]. Therefore, SNRPN may have a role in PWS. Methylation imprints have also been found at two other loci in 15q11-q13, PW71 [4] and D15S9 [5], which map 120 kb and 1.5 Mb proximal to SNRPN, respectively. We have now characterized in detail the gene structure and expression from two imprinted loci within 15q11-q13, SNRPN and D15S9, which suggests that both loci are surprisingly complex, with important implications for the pathogenesis of PWS.
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Katz, David J., Michael A. Beer, John M. Levorse, and Shirley M. Tilghman. "Functional Characterization of a Novel Ku70/80 Pause Site at the H19/Igf2 Imprinting Control Region." Molecular and Cellular Biology 25, no. 10 (2005): 3855–63. http://dx.doi.org/10.1128/mcb.25.10.3855-3863.2005.
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ABSTRACT The imprinted expression of the H19 and Igf2 genes in the mouse is controlled by an imprinting control center (ICR) whose activity is regulated by parent-of-origin differences in methylation. The only protein that has been implicated in ICR function is the zinc-finger protein CTCF, which binds at multiple sites within the maternally inherited ICR and is required to form a chromatin boundary that inhibits Igf2 expression. To identify other proteins that play a role in imprinting, we employed electrophoresis mobility shift assays to identify two novel binding sites within the ICR. The DNA binding activity was identified as the heterodimer Ku70/80, which binds nonspecifically to free DNA ends. The sites within the ICR bind Ku70/80 in a sequence-specific manner and with higher affinity than previously reported binding sites. The binding required the presence of Mg2+, implying that the sequence is a pause site for Ku70/80 translocation from a free end. Chromatin immunoprecipitation assays were unable to confirm that Ku70/80 binds to the ICR in vivo. In addition, mutation of these binding sites in the mouse did not result in any imprinting defects. A genome scan revealed that the binding site is found in LINE-1 retrotransposons, suggesting a possible role for Ku70/80 in transposition.
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Diederich, M., J. Heinzmann, W. Kues, et al. "164 EPIGENETIC ANALYSIS OF GENOMIC DNA IN PREPUBERAL AND ADULT BOVINE OOCYTES." Reproduction, Fertility and Development 23, no. 1 (2011): 184. http://dx.doi.org/10.1071/rdv23n1ab164.
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The use of oocytes obtained from prepuberal cattle shortens the generation interval by producing descendants of genetically valuable animals before achieving actual cultivation maturity. However, several studies proved that oocytes derived from prepuberal animals differ significantly from oocytes of adult animals with regard to their developmental capability and therefore reproductive potential. Epigenetic events are taken into consideration as a possible reason for this phenomenon. Particularly DNA methylation, allele specific gene expression in a parent-of-origin-specific manner (imprinting), and certain histone modifications, like acetylations, carboxylations, and phosphorylations, play an important role. This project aims to gain knowledge about the mechanisms involved in attaining of the full developmental potential of bovine oocytes. Using immature and in vitro matured oocytes of prepuberal and adult cattle, a comparative study was conducted by measuring mRNA expression of 4 developmentally relevant, but non-imprinted genes (GDF9, GLUT1, PRDX1, and ZAR1) as well as the general DNA methylation status, performed by bisulfite sequencing of 2 satellite sequences [bovine testis satellite I DNA segment 2 (BTSS2) and Bos taurus α satellite I DNA (BTS)]. After various pretreatments, immature bovine oocytes were collected from prepuberal calves [6–9 months, either left untreated (Ca1) or treated with FSH (Ca2) or FSH+IGF1 (Ca3) or FSH+IGFK (Ca4)] and adult animals [≥2nd lactation, either left untreated (Ad1) or treated with FSH (Ad2)] using the Ovum-pick-up (OPU) technique. The Ad1 group was considered the control group. First results of the qPCR analyses of immature oocytes show differences between treatment groups for GLUT1, PRDX1, and ZAR1 transcripts. Compared with Ad1, GLUT1 expression increased in Ad2 [fold change (FC) 2.2], Ca1 (FC 2.0), Ca2 (FC 1.8), and Ca3 (FC 1.4). The genes PRDX1 and ZAR1 were reduced in all groups by 0.02 to 0.07 in comparison with Ad1. The GDF9 showed generally a very low expression. The methylation analysis shows for BTSS2 and BTS significant differences before and after in vitro maturation in the groups Ad1 (BTSS2: 49.6 v. 64.9%), Ad2 (BTS: 76.7 v. 52.5%), Ca1 (BTSS2: 74.6 v. 53.3%), Ca2 (BTS: 72.8 v. 57.8%) and Ca3 (BTSS2: 60.6 v. 71.7%). Currently, the first experiment and statistical analysis are under way. The preliminary data confirm differences in gene expression between prepuberal and adult animals, and demonstrates the dependence of the methylation pattern on age and maturation status. These results contribute to a better understanding of the developmental potential of prepuberal oocytes in order to optimize their use for in vitro production of embryos. This work was supported by the H. Wilhelm Schaumann Foundation, Hamburg.
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Morgan, H. D., Y. Li, and C. O'Neill. "127. EPIGENETIC REPROGRAMMING IN ZYGOTES INVOLVES THE GLOBAL CYTOSINE DEMETHYLATION OF BOTH THE PATERNAL AND MATERNAL GENOMES." Reproduction, Fertility and Development 21, no. 9 (2009): 46. http://dx.doi.org/10.1071/srb09abs127.
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Epigenetic reprogramming is essential for normal development and has been held to occur in a different manner for the paternally and maternally inherited genomes. The current paradigm implicates active global demethylation of the paternal pronucleus soon after fertlization, but passive demethylation of maternally-derived genome over many cell-cycles. This parent-of-origin difference has been difficult to reconcile with other biological processes prompting us to re-examine this evidence. DNA methylation levels were examined in mouse zygotes by immunolocalization with methylcytosine specific antibodies. Zygotes were isolated from the oviduct at times after hCG and staged for pronuclei maturity (PN1-5, least to most mature) or metaphase commencement. We found methylation levels to be high in PN1-2 stage pronuclei but then progressively declined. By PN5 stage methylcytosine staining was greatly diminished. Yet, contrary to the current paradigm, demethylation generally occurred in both the male and female pronucleus. We found no methylcytosine staining in any metaphase chromosomes. The contrast of our results with those widely cited prompted us to review the methodology previously used. In previous studies zygotes that had been collected after fertilization and then cultured in vitro, or produced by IVF and then cultured were used. When we prepared zygotes by these methods we found that many PN5-stage cultured zygotes displayed relatively more demethylation of the male pronucleus than the female. When zygotes were generated by IVF this asynchrony was further exacerbated. In contrast to the zygotes collected directly from the reproductive tract, metaphase chromosomes in cultured post-syngamal zygotes commonly showed extensive methylcytosine staining. Our results show that the normal process of epigenetic reprogramming in the mouse involves global demethylation of both the paternal and maternal genomes. This was variably perturbed (particularly in the female pronucleus) by IVF and zygote culture.
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Pant, V. "The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains." Genes & Development 17, no. 5 (2003): 586–90. http://dx.doi.org/10.1101/gad.254903.
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Tiwari, M., N. Rawat, P. Vats, et al. "89 METHYLATION STATUS OF IGF2/H19 DMR3 REGION AFFECTS IN VITRO BLASTOCYST PRODUCTION IN GOAT (CAPRA HIRCUS)." Reproduction, Fertility and Development 29, no. 1 (2017): 152. http://dx.doi.org/10.1071/rdv29n1ab89.
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Parthenogenesis has been observed in lower animals but no known instance has been reported in mammals because both maternal and paternal genomes are a fundamental prerequisite for embryogenesis. A major reason for developmental failure of uniparental zygotes is expression of certain genes in a parent-of-origin-specific manner, i.e. genomic imprinting of genes. Out of many imprinted genes identified so far, IGF2/H19 have been extensively studied and known to play an important role in fetal and placental development. Gene IGF2 is expressed by the paternal allele, H19 is transcribed from the maternal allele, and the reciprocal expression of both genes is regulated by the DMR3 region placed upstream of the H19 gene. In the present study we compared the methylation status of IGF2/H19 DMR in parthenogenetic activated (PA) and IVF goat (Capra hircus) blastocyst through bisulphite sequencing. For this, immature oocytes of usable quality were subjected to in vitro maturation and subsequently used for embryo production through parthenogenesis (n = 993) (by calcium ionophore and 6-DMAP activation) and IVF (n = 1096). It was found that embryo production rate at all the embryonic stages (2-cell, 4-cell, 8–16-cell, morula, and blastocyst) was significantly higher (P < 0.05) in parthenogenesis (74.66 ± 3.35%, 61.90 ± 2.73%, 47.83 ± 2.95%, 38.13 ± 5.28%, and 21.11 ± 2.51%, respectively) as compared with IVF (55.21 ± 2.02%, 38.12 ± 2.48%, 28.53 ± 1.67%, 21.57 ± 1.59%, and 8.23 ± 1.02%, respectively). When blastocysts (n = 6 each) were subjected to TUNEL, it was found that PA blastocyst showed significantly higher (P < 0.05) total cell number (217.83 ± 18.80 v. 159.67 ± 13.94) and significantly low (P < 0.05) apoptotic index (2.04 ± 0.25 v. 4.03 ± 0.29) as compared with IVF blastocysts. For the methylation pattern study, we analysed 17 CpG sites on the DMR3 region of the IGF2/H19 gene. Variable methylation pattern was observed within these CpG sites in different clones (n = 15) of PA and IVF blastocyst. The DMR3 region of the IGF2/H19 gene was significantly hypermethylated (P < 0.05) in PA blastocysts as compared with IVF blastocysts (80.39 ± 2.96, 32.55 ± 4.37, respectively), which suggests higher expression of IGF2 in parthenotes. The result suggests IGF2 might play different roles in different species; the same expression pattern of IGF2 is observed in ovine, but a contrary result is found in porcine species. Our results signify the hypermethylation of IGF2/H19 DMR3, which leads to higher expression of IGF2 to support embryonic development at the blastocyst stage. This work was supported by the NFBSFARA Project on Parthenogenetic Goat (CA-4002), New Delhi, India.
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Shin, Dong-Myung, Ewa Zuba-Surma, Rui Liu, Mariusz Z. Ratajczak, and Magdalena Kucia. "Genetic and Epigenetic Studies Reveal That Murine Oct-4+ Very Small Embryonic/Epiblast-Like Stem Cells (VSELs) Present in Adult Tissues Share Several Similarities/Markers with Epiblast-Derived Migratory Primordial Germ Cells (PGCs)." Blood 114, no. 22 (2009): 2521. http://dx.doi.org/10.1182/blood.v114.22.2521.2521.
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Abstract Abstract 2521 Poster Board II-498 Recently, we identified a population of pluripotent VSELs in murine adult bone marrow (BM; Leukemia 2006:20;857). Compared with other adult stem cells (SCs), VSELs show unique epigenetic features including: i) open chromatin structures in the promoter of Oct-4 and Nanog; and ii) parent-of-origin-specific reprogramming of genomic imprinting. These features explain the pluripotent embryonic-like nature and quiescent status of these cells, respectively (Leukemia 2009:In press), and indicate their relation to an epiblast/germ-line pluripotent (P)SC population. To better understand the developmental origin of VSELs, we examined gene expression profiles and the epigenetic status of epiblast and germ-line related genes in these cells. We employed real time quantitative PCR (RQ-PCR) to evaluate gene expression, a bisulfite sequencing strategy to evaluate DNA methylation, and chromatin immunoprecipitation (ChIP) to elucidate histone codes in genes of interest. VSELs were isolated from murine BM by multiparameter fluorescence-activated cell sorter (FACS) as a population of Sca+lin−CD45− along with Sca+lin−CD45+ hematopoietic (H)SCs and BM mononuclear cells (MNCs). We noticed that VSELs, similarly to epiblast PSCs (EpiSCs), highly express the stemness genes (e.g., Oct-4, Nanog, Sox2, Klf4) and epiblast markers (Gbx2, Fgf5, Nodal). However, the Rex1 gene is expressed at a lower level compared to the murine ESC-D3 line. Moreover, VSELs also highly express the Stella, Blimp1, Dnd1, and Nanos3, which are developmental regulators during specification in the proximal epiblast of PGCs. Accordingly, the Stella promoter in VSELs was partially demethylated and highly enriched for transcriptionally active histones (acetylated H3, trimethylated lysine4 of H3) while being simultaneously less enriched for repressive ones (dimethylated lysine9 and trimethylated lysine27 of H3). In particular, we noticed that VSELs resemble migratory PGCs. To support this notion, VSELs: i) express several markers of migratory PGCs (Dppa2, Dppa4, Mvh); ii) do not express post-migratory PGCs genes (Dazl, Sycp3); and iii) have reprogrammed DNA demethylation in the repetitive sequence (LINE1) and the promoters of Mvh, Dazal, and Sycp3. Finally, VSELs express less the transcripts for cMyc, Stat3, Snai, and Ecat1, which are expressed in early specified PGCs. In conclusion, our previous data showing reprogramming of genomic imprinting in VSELs with the present gene expression profile and epigenetic studies strongly supports VSELs developmentally originating from epiblast-derived germ-line SCs (PGCs), particularly migratory PGCs. We believe VSELs are deposited during embryogenesis in the adult tissues as a backup for tissue-committed SCs and that epigenetic reprogramming tightly controls their proliferative potential. Thus, identification of mechanisms that control and modify the epigenetic marks in VSELs will be crucial for developing more powerful strategies to “unleash the power” of these cells and employ them in regenerative medicine. Disclosures: No relevant conflicts of interest to declare.
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Piedrahita, J., S. Bischoff, J. Estrada, et al. "263 USE OF PORCINE PARTHENOTES AND GENE EXPRESSION PROFILING USING MICROARRAYS FOR IDENTIFICATION OF IMPRINTED GENES." Reproduction, Fertility and Development 18, no. 2 (2006): 239. http://dx.doi.org/10.1071/rdv18n2ab263.
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Genomic imprinting arises from differential epigenetic markings including DNA methylation and histone modifications and results in one allele being expressed in a parent-of-origin specific manner. For further insight into the porcine epigenome, gene expression profiles of parthenogenetic (PRT; two maternally derived chromosome sets) and biparental embryos (BP; one maternal and one paternal set of chromosomes) were compared using microarrays. Comparison of the expression profiles of the two tissue types permits identification of both maternally and paternally imprinted genes and thus the degree of conservation of imprinted genes between swine and other mammalian species. Diploid porcine parthenogenetic fetuses were generated using follicular oocytes (BOMED, Madison, WI, USA). Oocytes with a visible polar body were activated using a single square pulse of direct current of 50 V/mm for 100 �s and diploidized by culture in 10 �g/mL cycloheximide for 6 h to limit extrusion of the second polar body. Following culture, BP embryos obtained by natural matings, and PRT embryos, were surgically transferred to oviducts on the first day of estrus. Fetuses recovered at 28-30 days of gestation were dissected to separate viscera including brain, liver, and placenta; the visceral tissues were then flash-frozen in liquid nitrogen. Porcine fibroblast tissue was obtained from the remaining carcass by mincing, trypsinization, and plating cells in �-MEM. Total RNA was extracted from frozen tissue or cell culture using RNA Aqueous kit (Ambion, Austin, TX, USA) according to the manufacturer's protocol. Gene expression differences between BP and PRT tissues were determined using the GeneChip� Porcine Genome Array (Affymetrix, Santa Clara, CA) containing 23 256 transcripts from Sus scrofa and representing 42 genes known to be imprinted in human and/or mice. Triplicate arrays were utilized for each tissue type, and for PRT versus BP combination. Significant differential gene expression was identified by a linear mixed model analysis using SAS 5.0 (SAS Institute, Cary, NC, USA). Storey's q-value method was used to correct for multiple testing at q d 0.05. The following genes were classified as imprinted on the basis of their expression profiles: In fibroblasts, ARHI, HTR2A, MEST, NDN, NNAT, PEG3, PLAGL1, PEG10, SGCE, SNRPN, and UBE3A; in liver, IGF2, PEG3, PLAGL1, PEG10, and SNRPN; in placenta, HTR2A, IGF2, MEST, NDN, NNAT, PEG3, PLAGL1, PEG10, and SNRPN; and in brain, none. Additionally, several genes not known to be imprinted in humans/mice were highly differentially expressed between the two tissue types. Overall, utilizing the PRT models and gene expression profiles, we have identified thirteen genes where imprinting is conserved between swine and humans/mice, and several candidate genes that represent potentially imprinted genes. Presently, our efforts are focused in the identification of single nucleotide polymorphisms (SNPs) to more carefully evaluate the behavior of these genes in normal and abnormal gestations and to test whether the candidate genes are indeed imprinted. This research was supported by USDA-CSREES grant 524383 to J. P. and B. F.
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Remnant, Emily J., Alyson Ashe, Paul E. Young, et al. "Parent-of-origin effects on genome-wide DNA methylation in the Cape honey bee (Apis mellifera capensis) may be confounded by allele-specific methylation." BMC Genomics 17, no. 1 (2016). http://dx.doi.org/10.1186/s12864-016-2506-8.
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Pignatta, Daniela, Robert M. Erdmann, Elias Scheer, Colette L. Picard, George W. Bell, and Mary Gehring. "Natural epigenetic polymorphisms lead to intraspecific variation in Arabidopsis gene imprinting." eLife 3 (July 3, 2014). http://dx.doi.org/10.7554/elife.03198.
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Imprinted gene expression occurs during seed development in plants and is associated with differential DNA methylation of parental alleles, particularly at proximal transposable elements (TEs). Imprinting variability could contribute to observed parent-of-origin effects on seed development. We investigated intraspecific variation in imprinting, coupled with analysis of DNA methylation and small RNAs, among three Arabidopsis strains with diverse seed phenotypes. The majority of imprinted genes were parentally biased in the same manner among all strains. However, we identified several examples of allele-specific imprinting correlated with intraspecific epigenetic variation at a TE. We successfully predicted imprinting in additional strains based on methylation variability. We conclude that there is standing variation in imprinting even in recently diverged genotypes due to intraspecific epiallelic variation. Our data demonstrate that epiallelic variation and genomic imprinting intersect to produce novel gene expression patterns in seeds.
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Dittrich, B�rbel, WendyP Robinson, Hans Knoblauch, et al. "Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13." Human Genetics 90, no. 3 (1992). http://dx.doi.org/10.1007/bf00220089.
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Kobayashi, Hisato. "Canonical and Non-canonical Genomic Imprinting in Rodents." Frontiers in Cell and Developmental Biology 9 (August 5, 2021). http://dx.doi.org/10.3389/fcell.2021.713878.
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Genomic imprinting is an epigenetic phenomenon that results in unequal expression of homologous maternal and paternal alleles. This process is initiated in the germline, and the parental epigenetic memories can be maintained following fertilization and induce further allele-specific transcription and chromatin modifications of single or multiple neighboring genes, known as imprinted genes. To date, more than 260 imprinted genes have been identified in the mouse genome, most of which are controlled by imprinted germline differentially methylated regions (gDMRs) that exhibit parent-of-origin specific DNA methylation, which is considered primary imprint. Recent studies provide evidence that a subset of gDMR-less, placenta-specific imprinted genes is controlled by maternal-derived histone modifications. To further understand DNA methylation-dependent (canonical) and -independent (non-canonical) imprints, this review summarizes the loci under the control of each type of imprinting in the mouse and compares them with the respective homologs in other rodents. Understanding epigenetic systems that differ among loci or species may provide new models for exploring genetic regulation and evolutionary divergence.
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Wanigasuriya, Iromi, Quentin Gouil, Sarah A. Kinkel, et al. "Smchd1 is a maternal effect gene required for genomic imprinting." eLife 9 (November 13, 2020). http://dx.doi.org/10.7554/elife.55529.
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Genomic imprinting establishes parental allele-biased expression of a suite of mammalian genes based on parent-of-origin specific epigenetic marks. These marks are under the control of maternal effect proteins supplied in the oocyte. Here we report epigenetic repressor Smchd1 as a novel maternal effect gene that regulates the imprinted expression of ten genes in mice. We also found zygotic SMCHD1 had a dose-dependent effect on the imprinted expression of seven genes. Together, zygotic and maternal SMCHD1 regulate three classic imprinted clusters and eight other genes, including non-canonical imprinted genes. Interestingly, the loss of maternal SMCHD1 does not alter germline DNA methylation imprints pre-implantation or later in gestation. Instead, what appears to unite most imprinted genes sensitive to SMCHD1 is their reliance on polycomb-mediated methylation as germline or secondary imprints, therefore we propose that SMCHD1 acts downstream of polycomb imprints to mediate its function.