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1
Taylor, Bethany C., and Nicolas L. Young. "Combinations of histone post-translational modifications." Biochemical Journal 478, no. 3 (2021): 511–32. http://dx.doi.org/10.1042/bcj20200170.
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Histones are essential proteins that package the eukaryotic genome into its physiological state of nucleosomes, chromatin, and chromosomes. Post-translational modifications (PTMs) of histones are crucial to both the dynamic and persistent regulation of the genome. Histone PTMs store and convey complex signals about the state of the genome. This is often achieved by multiple variable PTM sites, occupied or unoccupied, on the same histone molecule or nucleosome functioning in concert. These mechanisms are supported by the structures of ‘readers’ that transduce the signal from the presence or absence of PTMs in specific cellular contexts. We provide background on PTMs and their complexes, review the known combinatorial function of PTMs, and assess the value and limitations of common approaches to measure combinatorial PTMs. This review serves as both a reference and a path forward to investigate combinatorial PTM functions, discover new synergies, and gather additional evidence supporting that combinations of histone PTMs are the central currency of chromatin-mediated regulation of the genome.
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Zhiteneva, Alisa, Juan Jose Bonfiglio, Alexandr Makarov, et al. "Mitotic post-translational modifications of histones promote chromatin compaction in vitro." Open Biology 7, no. 9 (2017): 170076. http://dx.doi.org/10.1098/rsob.170076.
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How eukaryotic chromosomes are compacted during mitosis has been a leading question in cell biology since the nineteenth century. Non-histone proteins such as condensin complexes contribute to chromosome shaping, but appear not to be necessary for mitotic chromatin compaction. Histone modifications are known to affect chromatin structure. As histones undergo major changes in their post-translational modifications during mitotic entry, we speculated that the spectrum of cell-cycle-specific histone modifications might contribute to chromosome compaction during mitosis. To test this hypothesis, we isolated core histones from interphase and mitotic cells and reconstituted chromatin with them. We used mass spectrometry to show that key post-translational modifications remained intact during our isolation procedure. Light, atomic force and transmission electron microscopy analysis showed that chromatin assembled from mitotic histones has a much greater tendency to aggregate than chromatin assembled from interphase histones, even under low magnesium conditions where interphase chromatin remains as separate beads-on-a-string structures. These observations are consistent with the hypothesis that mitotic chromosome formation is a two-stage process with changes in the spectrum of histone post-translational modifications driving mitotic chromatin compaction, while the action of non-histone proteins such as condensin may then shape the condensed chromosomes into their classic mitotic morphology.
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Drury, Georgina E., Adam A. Dowle, David A. Ashford, Wanda M. Waterworth, Jerry Thomas, and Christopher E. West. "Dynamics of plant histone modifications in response to DNA damage." Biochemical Journal 445, no. 3 (2012): 393–401. http://dx.doi.org/10.1042/bj20111956.
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DNA damage detection and repair take place in the context of chromatin, and histone proteins play important roles in these events. Post-translational modifications of histone proteins are involved in repair and DNA damage signalling processes in response to genotoxic stresses. In particular, acetylation of histones H3 and H4 plays an important role in the mammalian and yeast DNA damage response and survival under genotoxic stress. However, the role of post-translational modifications to histones during the plant DNA damage response is currently poorly understood. Several different acetylated H3 and H4 N-terminal peptides following X-ray treatment were identified using MS analysis of purified histones, revealing previously unseen patterns of histone acetylation in Arabidopsis. Immunoblot analysis revealed an increase in the relative abundance of the H3 acetylated N-terminus, and a global decrease in hyperacetylation of H4 in response to DNA damage induced by X-rays. Conversely, mutants in the key DNA damage signalling factor ATM (ATAXIA TELANGIECTASIA MUTATED) display increased histone acetylation upon irradiation, linking the DNA damage response with dynamic changes in histone modification in plants.
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García‐Giménez, José Luis, Carlos Romá‐Mateo, and Federico V. Pallardó. "Oxidative post‐translational modifications in histones." BioFactors 45, no. 5 (2019): 641–50. http://dx.doi.org/10.1002/biof.1532.
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Corujo, David, and Marcus Buschbeck. "Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer." Cancers 10, no. 3 (2018): 59. http://dx.doi.org/10.3390/cancers10030059.
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Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.
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Yu, Yucong, Hong Wen, and Xiaobing Shi. "Histone mimics: more tales to read." Biochemical Journal 478, no. 14 (2021): 2789–91. http://dx.doi.org/10.1042/bcj20210357.
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Post-translational modifications (PTMs) on histone proteins are known as epigenetic marks that demarcate the status of chromatin. These modifications are ‘read' by specific reader proteins, which in turn recruit additional factors to modulate chromatin accessibility and the activity of the underlying DNA. Accumulating evidence suggests that these modifications are not restricted solely to histones, many non-histone proteins may function in a similar way through mimicking the histones. In this commentary, we briefly discuss a systematic study of the discovery of histone H3 N-terminal mimicry proteins (H3TMs), and their implications in chromatin regulation and drug discoveries.
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Liu, Wallace H., and Mair E. A. Churchill. "Histone transfer among chaperones." Biochemical Society Transactions 40, no. 2 (2012): 357–63. http://dx.doi.org/10.1042/bst20110737.
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The eukaryotic processes of nucleosome assembly and disassembly govern chromatin dynamics, in which histones exchange in a highly regulated manner to promote genome accessibility for all DNA-dependent processes. This regulation is partly carried out by histone chaperones, which serve multifaceted roles in co-ordinating the interactions of histone proteins with modification enzymes, nucleosome remodellers, other histone chaperones and nucleosomal DNA. The molecular details of the processes by which histone chaperones promote delivery of histones among their many functional partners are still largely undefined, but promise to offer insights into epigenome maintenance. In the present paper, we review recent findings on the histone chaperone interactions that guide the assembly of histones H3 and H4 into chromatin. This evidence supports the concepts of histone post-translational modifications and specific histone chaperone interactions as guiding principles for histone H3/H4 transactions during chromatin assembly.
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Hamam and Palaniyar. "Post-Translational Modifications in NETosis and NETs-Mediated Diseases." Biomolecules 9, no. 8 (2019): 369. http://dx.doi.org/10.3390/biom9080369.
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: Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases.
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Barnes, Claire E., David M. English, and Shaun M. Cowley. "Acetylation & Co: an expanding repertoire of histone acylations regulates chromatin and transcription." Essays in Biochemistry 63, no. 1 (2019): 97–107. http://dx.doi.org/10.1042/ebc20180061.
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Abstract Packaging the long and fragile genomes of eukaryotic species into nucleosomes is all well and good, but how do cells gain access to the DNA again after it has been bundled away? The solution, in every species from yeast to man, is to post-translationally modify histones, altering their chemical properties to either relax the chromatin, label it for remodelling or make it more compact still. Histones are subject to a myriad of modifications: acetylation, methylation, phosphorylation, ubiquitination etc. This review focuses on histone acylations, a diverse group of modifications which occur on the ε-amino group of Lysine residues and includes the well-characterised Lysine acetylation. Over the last 50 years, histone acetylation has been extensively characterised, with the discovery of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and global mapping experiments, revealing an association of hyperacetylated histones with accessible, transcriptionally active chromatin. More recently, there has been an explosion in the number of unique short chain ‘acylations’ identified by MS, including: propionylation, butyrylation, crotonylation, succinylation, malonylation and 2-hydroxyisobutyrylation. These novel modifications add a range of chemical environments to histones, and similar to acetylation, appear to accumulate at transcriptional start sites and correlate with gene activity.
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MERSCH, Marjorie, Sarah-Anne DAVID, Anaïs VITORINO CARVALHO, et al. "Apports du séquençage haut-débit sur la connaissance de l'épigénome aviaire." INRA Productions Animales 31, no. 4 (2019): 325–36. http://dx.doi.org/10.20870/productions-animales.2018.31.4.2372.
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Comme toutes les espèces de rente, les oiseaux d'élevage ont été sélectionnés génétiquement afin d’augmenter leurs performances. Cependant, de nombreuses études ont montré que le phénotype d’un individu n’est pas le simple résultat de son patrimoine génétique. En effet, il est également sensible aux variations de l’environnement (température, nutrition…) qui peuvent notamment induire des altérations de marques épigénétiques aboutissant à des changements durables des programmes d’expression de gènes. Il est donc essentiel de comprendre comment les épigénomes sont régulés afin d’envisager de futurs leviers ou marqueurs d’adaptation des animaux. Aujourd’hui, le séquençage à haut-débit est devenu relativement abordable et les outils bio-informatiques matures pour envisager l’étude des marques épigénétiques à l'échelle du génome. Chez les oiseaux, un nombre croissant d'études utilisent ces technologies à haut-débit pour explorer les mécanismes épigénétiques impliqués dans des processus tels que l'immunité ou l'adaptation à l’environnement. Dans cette synthèse, nous décrivons en quoi ces technologies ont contribué à enrichir les connaissances sur l'épigénome aviaire et plus particulièrement celui du poulet, en nous focalisant sur les deux types de modifications épigénétiques les plus étudiées, la méthylation de l'ADN et les modifications post-traductionnelles des histones. Nous présentons également les concepts nécessaires à la conception et la réalisation des analyses haut-débit des épigénomes aviaires. En plus des connaissances fondamentales fortement attendues par la communauté scientifique, une meilleure compréhension des mécanismes épigénétiques à l’origine de la régulation de l’expression génique en réponse aux modifications environnementales chez l’oiseau pourrait contribuer au développement d’une production avicole durable.
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Mushtaq, Arjamand, Ulfat Syed Mir, Clayton R. Hunt, et al. "Role of Histone Methylation in Maintenance of Genome Integrity." Genes 12, no. 7 (2021): 1000. http://dx.doi.org/10.3390/genes12071000.
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Packaging of the eukaryotic genome with histone and other proteins forms a chromatin structure that regulates the outcome of all DNA mediated processes. The cellular pathways that ensure genomic stability detect and repair DNA damage through mechanisms that are critically dependent upon chromatin structures established by histones and, particularly upon transient histone post-translational modifications. Though subjected to a range of modifications, histone methylation is especially crucial for DNA damage repair, as the methylated histones often form platforms for subsequent repair protein binding at damaged sites. In this review, we highlight and discuss how histone methylation impacts the maintenance of genome integrity through effects related to DNA repair and repair pathway choice.
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Kolarz, Bogdan, and Maria Majdan. "Epigenetic determinants in rheumatoid arthritis: the influence of DNA methylation and histone modifications." Postępy Higieny i Medycyny Doświadczalnej 71 (December 22, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.7478.
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Epigenetics is a field of science which describes external and environmental modifications to DNA without altering their primary sequences of nucleotides. Contrary to genetic changes, epigenetic modifications are reversible. The epigenetic changes appear as a result of the influence of external factors, such as diet or stress. Epigenetic mechanisms alter the accessibility of DNA by methylation of DNA or post-translational modifications of histones (acetylation, methylation, phosphorylation, ubiquitinqation). The extent of DNA methylation depends on the balance between DNA methyltransferases and demethylases. The main histone modifications are stimulated by K-acetyltransferases, histone deacetylases, K-metyltransferases and K-demethylases. There is proof that environmental modifications of this enzymes regulate immunological processes including autoimmunity in rheumatoid arthritis (RA). In this work we present epigenetic mechanisms involved in RA pathogenesis and a range of research presenting the possible impact of its modification in RA patients.
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Andrés, Marta, Daniel García-Gomis, Inma Ponte, Pedro Suau, and Alicia Roque. "Histone H1 Post-Translational Modifications: Update and Future Perspectives." International Journal of Molecular Sciences 21, no. 16 (2020): 5941. http://dx.doi.org/10.3390/ijms21165941.
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Histone H1 is the most variable histone and its role at the epigenetic level is less characterized than that of core histones. In vertebrates, H1 is a multigene family, which can encode up to 11 subtypes. The H1 subtype composition is different among cell types during the cell cycle and differentiation. Mass spectrometry-based proteomics has added a new layer of complexity with the identification of a large number of post-translational modifications (PTMs) in H1. In this review, we summarize histone H1 PTMs from lower eukaryotes to humans, with a particular focus on mammalian PTMs. Special emphasis is made on PTMs, whose molecular function has been described. Post-translational modifications in H1 have been associated with the regulation of chromatin structure during the cell cycle as well as transcriptional activation, DNA damage response, and cellular differentiation. Additionally, PTMs in histone H1 that have been linked to diseases such as cancer, autoimmune disorders, and viral infection are examined. Future perspectives and challenges in the profiling of histone H1 PTMs are also discussed.
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Krejčí, Jana, Lenka Stixová, Eva Pagáčová, et al. "Post-Translational Modifications of Histones in Human Sperm." Journal of Cellular Biochemistry 116, no. 10 (2015): 2195–209. http://dx.doi.org/10.1002/jcb.25170.
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Liu, Yanli, and Jinrong Min. "Structure and function of histone methylation-binding proteins in plants." Biochemical Journal 473, no. 12 (2016): 1663–80. http://dx.doi.org/10.1042/bcj20160123.
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Post-translational modifications of histones play important roles in modulating many essential biological processes in both animals and plants. These covalent modifications, including methylation, acetylation, phosphorylation, ubiquitination, SUMOylation and so on, are laid out and erased by histone-modifying enzymes and read out by effector proteins. Recent studies have revealed that a number of developmental processes in plants are under the control of histone post-translational modifications, such as floral transition, seed germination, organogenesis and morphogenesis. Therefore, it is critical to identify those protein domains, which could specifically recognize these post-translational modifications to modulate chromatin structure and regulate gene expression. In the present review, we discuss the recent progress in understanding the structure and function of the histone methylation readers in plants, by focusing on Arabidopsis thaliana proteins.
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Nightingale, Karl P., Susanne Gendreizig, Darren A. White, Charlotte Bradbury, Florian Hollfelder, and Bryan M. Turner. "Cross-talk between Histone Modifications in Response to Histone Deacetylase Inhibitors." Journal of Biological Chemistry 282, no. 7 (2006): 4408–16. http://dx.doi.org/10.1074/jbc.m606773200.
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Histones are subject to a wide variety of post-translational modifications that play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation, histone H3 acetylation and H3 lysine 4 methylation, are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the “degree” of H3K4 methylation, plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments and in vitro methyltransferase assays shows that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities, the methyltransferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.
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Cosgrove, Michael S., and Cynthia Wolberger. "How does the histone code work?" Biochemistry and Cell Biology 83, no. 4 (2005): 468–76. http://dx.doi.org/10.1139/o05-137.
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Patterns of histone post-translational modifications correlate with distinct chromosomal states that regulate access to DNA, leading to the histone-code hypothesis. However, it is not clear how modification of flexible histone tails leads to changes in nucleosome dynamics and, thus, chromatin structure. The recent discovery that, like the flexible histone tails, the structured globular domain of the nucleosome core particle is also extensively modified adds a new and exciting dimension to the histone-code hypothesis, and calls for the re-examination of current models for the epigenetic regulation of chromatin structure. Here, we review these findings and other recent studies that suggest the structured globular domain of the nucleosome core particle plays a key role regulating chromatin dynamics.Key words: histones, histone code, modifications, epigenetic, chromatin, nucleosome, dynamics, regulated nucleosome mobility, core, archaeal, combinatorial switch, histone octamer.
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Molina-Serrano, Diego, Vassia Schiza, and Antonis Kirmizis. "Cross-talk among epigenetic modifications: lessons from histone arginine methylation." Biochemical Society Transactions 41, no. 3 (2013): 751–59. http://dx.doi.org/10.1042/bst20130003.
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Epigenetic modifications, including those occurring on DNA and on histone proteins, control gene expression by establishing and maintaining different chromatin states. In recent years, it has become apparent that epigenetic modifications do not function alone, but work together in various combinations, and cross-regulate each other in a manner that diversifies their functional states. Arginine methylation is one of the numerous PTMs (post-translational modifications) occurring on histones, catalysed by a family of PRMTs (protein arginine methyltransferases). This modification is involved in the regulation of the epigenome largely by controlling the recruitment of effector molecules to chromatin. Histone arginine methylation associates with both active and repressed chromatin states depending on the residue involved and the configuration of the deposited methyl groups. The present review focuses on the increasing number of cross-talks between histone arginine methylation and other epigenetic modifications, and describe how these cross-talks influence factor binding to regulate transcription. Furthermore, we present models of general cross-talk mechanisms that emerge from the examples of histone arginine methylation and allude to various techniques that help decipher the interplay among epigenetic modifications.
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Bronner, Christian, Guy Fuhrmann, Frédéric L. Chédin, Marcella Macaluso, and Sirano Dhe-Paganon. "UHRF1 Links the Histone Code and DNA Methylation to Ensure Faithful Epigenetic Memory Inheritance." Genetics & Epigenetics 2 (January 2009): GEG.S3992. http://dx.doi.org/10.4137/geg.s3992.
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Epigenetics is the study of the transmission of cell memory through mitosis or meiosis that is not based on the DNA sequence. At the molecular level the epigenetic memory of a cell is embedded in DNA methylation, histone post-translational modifications, RNA interference and histone isoform variation. There is a tight link between histone post-translational modifications (the histone code) and DNA methylation, as modifications of histones contribute to the establishment of DNA methylation patterns and vice versa. Interestingly, proteins have recently been identified that can simultaneously read both methylated DNA and the histone code. UHRF1 fulfills these requirements by having unique structural domains that allow concurrent recognition of histone modifications and methylated DNA. Herein, we review our current knowledge of UHRF1 and discuss how this protein ensures the link between histone marks and DNA methylation. Understanding the molecular functions of this protein may reveal the physiological relevance of the linkage between these layers of epigenetic marks.
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Galasinski, Scott C., Donna F. Louie, Kristen K. Gloor, Katheryn A. Resing, and Natalie G. Ahn. "Global Regulation of Post-translational Modifications on Core Histones." Journal of Biological Chemistry 277, no. 4 (2001): 2579–88. http://dx.doi.org/10.1074/jbc.m107894200.
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Bowman, Gregory D., and Michael G. Poirier. "Post-Translational Modifications of Histones That Influence Nucleosome Dynamics." Chemical Reviews 115, no. 6 (2014): 2274–95. http://dx.doi.org/10.1021/cr500350x.
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Draker, Ryan, and Peter Cheung. "Transcriptional and epigenetic functions of histone variant H2A.ZThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process." Biochemistry and Cell Biology 87, no. 1 (2009): 19–25. http://dx.doi.org/10.1139/o08-117.
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The chromatin organization of a genome ultimately dictates the gene expression profile of the cell. It is now well recognized that key mechanisms that regulate chromatin structure include post-translational modifications of histones and the incorporation of histone variants at strategic sites within the genome. H2A.Z is a variant of H2A that is localized to the 5′ end of many genes and is required for proper regulation of gene expression. However, its precise function in the transcription process is not yet well defined. In this review, we discuss some of the recent findings related to this histone variant, how it associates with other histone epigenetic marks, and how post-translational modifications of H2A.Z further define its function.
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Dilweg, Ivar W., and Remus T. Dame. "Post-translational modification of nucleoid-associated proteins: an extra layer of functional modulation in bacteria?" Biochemical Society Transactions 46, no. 5 (2018): 1381–92. http://dx.doi.org/10.1042/bst20180488.
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Post-translational modification (PTM) of histones has been investigated in eukaryotes for years, revealing its widespread occurrence and functional importance. Many PTMs affect chromatin folding and gene activity. Only recently the occurrence of such modifications has been recognized in bacteria. However, it is unclear whether PTM of the bacterial counterparts of eukaryotic histones, nucleoid-associated proteins (NAPs), bears a comparable significance. Here, we scrutinize proteome mass spectrometry data for PTMs of the four most abundantly present NAPs in Escherichia coli (H-NS, HU, IHF and FIS). This approach allowed us to identify a total of 101 unique PTMs in the 11 independent proteomic studies covered in this review. Combined with structural and genetic information on these proteins, we describe potential effects of these modifications (perturbed DNA-binding, structural integrity or interaction with other proteins) on their function.
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Pardal, Alonso J., Filipe Fernandes-Duarte, and Andrew J. Bowman. "The histone chaperoning pathway: from ribosome to nucleosome." Essays in Biochemistry 63, no. 1 (2019): 29–43. http://dx.doi.org/10.1042/ebc20180055.
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AbstractNucleosomes represent the fundamental repeating unit of eukaryotic DNA, and comprise eight core histones around which DNA is wrapped in nearly two superhelical turns. Histones do not have the intrinsic ability to form nucleosomes; rather, they require an extensive repertoire of interacting proteins collectively known as ‘histone chaperones’. At a fundamental level, it is believed that histone chaperones guide the assembly of nucleosomes through preventing non-productive charge-based aggregates between the basic histones and acidic cellular components. At a broader level, histone chaperones influence almost all aspects of chromatin biology, regulating histone supply and demand, governing histone variant deposition, maintaining functional chromatin domains and being co-factors for histone post-translational modifications, to name a few. In this essay we review recent structural insights into histone-chaperone interactions, explore evidence for the existence of a histone chaperoning ‘pathway’ and reconcile how such histone-chaperone interactions may function thermodynamically to assemble nucleosomes and maintain chromatin homeostasis.
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Lindroth, Anders M., Yoon Jung Park, Verónica Matía, and Massimo Squatrito. "The mechanistic GEMMs of oncogenic histones." Human Molecular Genetics 29, R2 (2020): R226—R235. http://dx.doi.org/10.1093/hmg/ddaa143.
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Abstract The last decade’s progress unraveling the mutational landscape of all age groups of cancer has uncovered mutations in histones as vital contributors of tumorigenesis. Here we review three new aspects of oncogenic histones: first, the identification of additional histone mutations potentially contributing to cancer formation; second, tumors expressing histone mutations to study the crosstalk of post-translational modifications, and; third, development of sophisticated biological model systems to reproduce tumorigenesis. At the outset, we recapitulate the firstly discovered histone mutations in pediatric and adolescent tumors of the brain and bone, which still remain the most pronounced histone alterations in cancer. We branch out to discuss the ramifications of histone mutations, including novel ones, that stem from altered protein-protein interactions of cognate histone modifiers as well as the stability of the nucleosome. We close by discussing animal models of oncogenic histones that reproduce tumor formation molecularly and morphologically and the prospect of utilizing them for drug testing, leading to efficient treatment and cure of deadly cancers with histone mutations.
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Jezek, Meagan, and Erin Green. "Histone Modifications and the Maintenance of Telomere Integrity." Cells 8, no. 2 (2019): 199. http://dx.doi.org/10.3390/cells8020199.
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Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. The integrity of telomeres is maintained by a coordinated network of proteins and RNAs, such as the telomerase holoenzyme and protective proteins that prevent the recognition of the telomere ends as a DNA double-strand breaks. The structure of chromatin at telomeres and within adjacent subtelomeres has been implicated in telomere maintenance pathways in model systems and humans. Specific post-translational modifications of histones, including methylation, acetylation, and ubiquitination, have been shown to be necessary for maintaining a chromatin environment that promotes telomere integrity. Here we review the current knowledge regarding the role of histone modifications in maintaining telomeric and subtelomeric chromatin, discuss the implications of histone modification marks as they relate to human disease, and highlight key areas for future research.
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Bernardes, Natalia Elisa, and Yuh Min Chook. "Nuclear import of histones." Biochemical Society Transactions 48, no. 6 (2020): 2753–67. http://dx.doi.org/10.1042/bst20200572.
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The transport of histones from the cytoplasm to the nucleus of the cell, through the nuclear membrane, is a cellular process that regulates the supply of new histones in the nucleus and is key for DNA replication and transcription. Nuclear import of histones is mediated by proteins of the karyopherin family of nuclear transport receptors. Karyopherins recognize their cargos through linear motifs known as nuclear localization/export sequences or through folded domains in the cargos. Karyopherins interact with nucleoporins, proteins that form the nuclear pore complex, to promote the translocation of their cargos into the nucleus. When binding to histones, karyopherins not only function as nuclear import receptors but also as chaperones, protecting histones from non-specific interactions in the cytoplasm, in the nuclear pore and possibly in the nucleus. Studies have also suggested that karyopherins might participate in histones deposition into nucleosomes. In this review we describe structural and biochemical studies from the last two decades on how karyopherins recognize and transport the core histone proteins H3, H4, H2A and H2B and the linker histone H1 from the cytoplasm to the nucleus, which karyopherin is the major nuclear import receptor for each of these histones, the oligomeric state of histones during nuclear import and the roles of post-translational modifications, histone-chaperones and RanGTP in regulating these nuclear import pathways.
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Picchi, Gisele F. A., Vanessa Zulkievicz, Marco A. Krieger, Nilson T. Zanchin, Samuel Goldenberg, and Lyris M. F. de Godoy. "Post-translational Modifications of Trypanosoma cruzi Canonical and Variant Histones." Journal of Proteome Research 16, no. 3 (2017): 1167–79. http://dx.doi.org/10.1021/acs.jproteome.6b00655.
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Beck, Hans Christian, Eva C. Nielsen, Rune Matthiesen, et al. "Quantitative Proteomic Analysis of Post-translational Modifications of Human Histones." Molecular & Cellular Proteomics 5, no. 7 (2006): 1314–25. http://dx.doi.org/10.1074/mcp.m600007-mcp200.
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Nowak-Imialek, M., C. Wrenzycki, D. Herrmann, et al. "258 MESSENGER RNA EXPRESSION PATTERNS OF HISTONE MODIFICATION GENES IN BOVINE EMBRYOS DERIVED FROM DIFFERENT ORIGINS." Reproduction, Fertility and Development 18, no. 2 (2006): 236. http://dx.doi.org/10.1071/rdv18n2ab258.
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Epigenetic modifications of the genome, such as covalent modifications of histones, are crucial for transcriptional regulation during development. The N-terminal tails of the histones are subject to post-translational modifications, including acetylation, deacetylation and methylation. histone acetylation loosens chromatin packing and correlates with transcriptional activation. The enzymes Histone acetyltransferases (HATs) transfer acetyl moieties to the lysine residues of histones H2A, H2B, H3, and H4. Histone acetylation is a reversible process which is catalyzed by the histone deacetylase (HDAC) and results in transcriptional repression. Histone methyltransferase (HMT) is responsible for the methylation of arginine in histones 3 and 4, playing an important role in transcriptional activation of genes. In contrast, the H3 Lys 9 methylation is associated with a transcriptionally repressive heterochromatin. The objective of the present study was to determine the effects of different origins of embryos on the relative abundance of transcripts for the histone acetyltransferase 1 (HAT1), histone deacetylase 2 (HDAC2), histone metyltransferases (SUV39H1 and G9A), and heterochromatin protein 1 (HP1). Messenger RNA expression profiles of these genes were investigated in bovine oocytes and pre-implantation embryos up to the blastocyt stage produced either in vitro by two different culture systems, i.e. SOF+BSA or TCM+SERUM, by somatic cloning using adult male and female fibroblasts, parthenogenetic activation, and androgenetic construction, or in vivo, employing semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Significant differences are described below. HAT1, SUV39H1, G9A, and HP1 mRNA transcripts decreased in enucleated oocytes, compared with immature oocytes. The relative abundance of HAT1 and SUV39H1 transcripts was significantly increased in NT-derived zygotes produced from adult female fibroblasts, compared to their in vitro fertilized and parthenogenetic counterparts. No differences were found in the relative abundances of gene transcripts at the 8-16-cell stage, except for parthenogenetic embryos in which SUV39H1 transcripts were significantly higher than in all other 8-16 cell groups. The relative abundance of SUV39H1, G9A, and HP1 transcripts were significantly higher in NT-derived blastocysts derived from adult male fibroblasts than in their in vivo-generated counterparts. HP1 and G9A transcript levels were significantly increased in NT-derived blastocysts derived from male fibroblasts compared to NT-derived embryos produced from female fibroblasts. The results show that the in vitro environment and the nuclear transfer protocol affect mRNA expression patterns of histone modification genes in pre-implantation bovine embryos.
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Pflum, Mary Kay H., Jeffrey K. Tong, William S. Lane, and Stuart L. Schreiber. "Histone Deacetylase 1 Phosphorylation Promotes Enzymatic Activity and Complex Formation." Journal of Biological Chemistry 276, no. 50 (2001): 47733–41. http://dx.doi.org/10.1074/jbc.m105590200.
Full textAbstract:
Accessibility of the genome to DNA-binding transcription factors is regulated by proteins that control the acetylation of amino-terminal lysine residues on nucleosomal histones. Specifically, histone deacetylase (HDAC) proteins repress transcription by deacetylating histones. To date, the only known regulatory mechanism of HDAC1 function is via interaction with associated proteins. Although the control of HDAC1 function by protein interaction and recruitment is well precedented, we were interested in exploring HDAC1 regulation by post-translational modification. Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser421and Ser423, were unambiguously identified. Loss of phosphorylation at Ser421and Ser423due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1. Deletion of the highly charged carboxyl-terminal region of HDAC1 also decreased its deacetylase activity and protein associations, revealing its requirement in maintaining HDAC1 function. Our results reinforce the importance of protein associations in modulating HDAC1 function and provide the first step toward characterizing the role of post-translational modifications in regulating HDAC activityin vivo.
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Dwivedi, Nishant, and Marko Radic. "Citrullination of autoantigens implicates NETosis in the induction of autoimmunity." Annals of the Rheumatic Diseases 73, no. 3 (2013): 483–91. http://dx.doi.org/10.1136/annrheumdis-2013-203844.
Full textAbstract:
Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins thus are crucial questions for understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death called NETosis deserves attention because it requires the post-translational modification of histones and results in the extracellular release of chromatin. NETosis received its name from NET, the acronym given to Neutrophil Extracellular Trap. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4). The deiminated chromatin may function to capture or ‘trap’ bacterial pathogens, thus generating an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalised by host phagocytes during acute inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance. Autoantibodies to deiminated histones are prevalent in Felty's syndrome patients and are present in systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). These observations clearly implicate histone deimination as an epigenetic mark that can act as an autoantibody stimulant.
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Harjivan, Shrika G., Catarina Charneira, Inês L. Martins, et al. "Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine." Molecules 26, no. 5 (2021): 1349. http://dx.doi.org/10.3390/molecules26051349.
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Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug’s bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.
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Th'ng, John PH. "Histone modifications and apoptosis: Cause or consequence?" Biochemistry and Cell Biology 79, no. 3 (2001): 305–11. http://dx.doi.org/10.1139/o01-031.
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Since the first description of apoptosis, genetic and biochemical studies have led to a greater understanding of the multiple pathways that eukaryotic cells can take to terminate their existence. These findings have also proven useful in understanding the development of various diseases such as AIDS, Alzheimer's, and Parkinson's and have provided potential targets for possible therapies. Despite all these studies, the mechanism of chromatin condensation, a morphological hallmark of apoptosis, remains elusive. This review describes the work to date on the post-translational modifications of histones during apoptosis and discusses the models that have been presented to explain the apoptotic condensation of chromatin.Key words: histones, nucleosomes, chromatin, apoptosis.
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Garcia, Benjamin A., Sandra B. Hake, Robert L. Diaz, et al. "Organismal Differences in Post-translational Modifications in Histones H3 and H4." Journal of Biological Chemistry 282, no. 10 (2006): 7641–55. http://dx.doi.org/10.1074/jbc.m607900200.
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Chen, Yue, Robert Sprung, Yi Tang, et al. "Lysine Propionylation and Butyrylation Are Novel Post-translational Modifications in Histones." Molecular & Cellular Proteomics 6, no. 5 (2007): 812–19. http://dx.doi.org/10.1074/mcp.m700021-mcp200.
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Garcia, Benjamin A., Jeffrey Shabanowitz, and Donald F. Hunt. "Characterization of histones and their post-translational modifications by mass spectrometry." Current Opinion in Chemical Biology 11, no. 1 (2007): 66–73. http://dx.doi.org/10.1016/j.cbpa.2006.11.022.
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Weaver, Tyler, Emma Morrison, and Catherine Musselman. "Reading More than Histones: The Prevalence of Nucleic Acid Binding among Reader Domains." Molecules 23, no. 10 (2018): 2614. http://dx.doi.org/10.3390/molecules23102614.
Full textAbstract:
The eukaryotic genome is packaged into the cell nucleus in the form of chromatin, a complex of genomic DNA and histone proteins. Chromatin structure regulation is critical for all DNA templated processes and involves, among many things, extensive post-translational modification of the histone proteins. These modifications can be “read out” by histone binding subdomains known as histone reader domains. A large number of reader domains have been identified and found to selectively recognize an array of histone post-translational modifications in order to target, retain, or regulate chromatin-modifying and remodeling complexes at their substrates. Interestingly, an increasing number of these histone reader domains are being identified as also harboring nucleic acid binding activity. In this review, we present a summary of the histone reader domains currently known to bind nucleic acids, with a focus on the molecular mechanisms of binding and the interplay between DNA and histone recognition. Additionally, we highlight the functional implications of nucleic acid binding in chromatin association and regulation. We propose that nucleic acid binding is as functionally important as histone binding, and that a significant portion of the as yet untested reader domains will emerge to have nucleic acid binding capabilities.
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Jiang, Lihua, Jonell N. Smith, Shannon L. Anderson, Ping Ma, Craig A. Mizzen, and Neil L. Kelleher. "Global Assessment of Combinatorial Post-translational Modification of Core Histones in Yeast Using Contemporary Mass Spectrometry." Journal of Biological Chemistry 282, no. 38 (2007): 27923–34. http://dx.doi.org/10.1074/jbc.m704194200.
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A global view of all core histones in yeast is provided by tandem mass spectrometry of intact histones H2A, H2B, H4, and H3. This allowed detailed characterization of >50 distinct histone forms and their semiquantitative assessment in the deletion mutants gcn5Δ, spt7Δ, ahc1Δ, and rtg2Δ, affecting the chromatin remodeling complexes SAGA, SLIK, and ADA. The “top down” mass spectrometry approach detected dramatic decreases in acetylation on H3 and H2B in gcn5Δ cells versus wild type. For H3 in wild type cells, tandem mass spectrometry revealed a direct correlation between increases of Lys4 trimethylation and the 0, 1, 2, and 3 acetylation states of histone H3. The results show a wide swing from 10 to 80% Lys4 trimethylation levels on those H3 tails harboring 0 or 3 acetylations, respectively. Reciprocity between these chromatin marks was apparent, since gcn5Δ cells showed a 30% decrease in trimethylation levels on Lys4 in addition to a decrease of acetylation levels on H3 in bulk chromatin. Deletion of Set1, the Lys4 methyltransferase, was associated with the linked disappearance of both Lys4 methylation and Lys14 and Lys18 or Lys23 acetylation on H3. In sum, we have defined the “basis set” of histone forms present in yeast chromatin using a current mass spectrometric approach that both quickly profiles global changes and directly probes the connectivity of modifications on the same histone.
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Robin, Philippe, Lauriane Fritsch, Ophélie Philipot, Fedor Svinarchuk, and Slimane Ait-Si-Ali. "Post-translational modifications of histones H3 and H4 associated with the histone methyltransferases Suv39h1 and G9a." Genome Biology 8, no. 12 (2007): R270. http://dx.doi.org/10.1186/gb-2007-8-12-r270.
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Castro, Kamilah, and Patrizia Casaccia. "Epigenetic modifications in brain and immune cells of multiple sclerosis patients." Multiple Sclerosis Journal 24, no. 1 (2018): 69–74. http://dx.doi.org/10.1177/1352458517737389.
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Multiple sclerosis (MS) is a debilitating neurological disease whose onset and progression are influenced by the interplay of genetic and environmental factors. Epigenetic modifications, which include post-translational modification of the histones and DNA, are considered mediators of gene–environment interactions and a growing body of evidence suggests that they play an important role in MS pathology and could be potential therapeutic targets. Since epigenetic events regulate transcription of different genes in a cell type–specific fashion, we caution on the distinct functional consequences that targeting the same epigenetic modifications might have in distinct cell types. In this review, we primarily focus on the role of histone acetylation and DNA methylation on oligodendrocyte and T-cell function and its potential implications for MS. We find that decreased histone acetylation and increased DNA methylation in oligodendrocyte lineage (OL) cells enhance myelin repair, which is beneficial for MS, while the same epigenetic processes in T cells augment their pro-inflammatory phenotype, which can exacerbate disease severity. In conclusion, epigenetic-based therapies for MS may have great value but only when cellular specificity is taken into consideration.
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Hurd, Paul J., Andrew J. Bannister, Karen Halls, et al. "Phosphorylation of Histone H3 Thr-45 Is Linked to Apoptosis." Journal of Biological Chemistry 284, no. 24 (2009): 16575–83. http://dx.doi.org/10.1074/jbc.m109.005421.
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Numerous post-translational modifications have been identified in histones. Most of these occur within the histone tails, but a few have been identified within the histone core sequences. Histone core post-translational modifications have the potential to directly modulate nucleosome structure and consequently DNA accessibility. Here, we identify threonine 45 of histone H3 (H3T45) as a site of phosphorylation in vivo. We find that phosphorylation of H3T45 (H3T45ph) increases dramatically in apoptotic cells, around the time of DNA nicking. To further explore this connection, we analyzed human neutrophil cells because they are short-lived cells that undergo apoptosis in vivo. Freshly isolated neutrophils contain very little H3T45ph, whereas cells cultured for 20 h possess significant amounts; the kinetics of H3T45ph induction closely parallel those of caspase-3 activation. Cytokine inhibition of neutrophil apoptosis leads to reduced levels of H3T45ph. We identify protein kinase C-δ as the kinase responsible for H3T45ph in vitro and in vivo. Given the nucleosomal position of H3T45, we postulate that H3T45ph induces structural change within the nucleosome to facilitate DNA nicking and/or fragmentation.
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Zhao, Linhong, Junaid Ali Shah, Yong Cai, and Jingji Jin. "‘O-GlcNAc Code’ Mediated Biological Functions of Downstream Proteins." Molecules 23, no. 8 (2018): 1967. http://dx.doi.org/10.3390/molecules23081967.
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As one of the post-translational modifications, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) often occurs on serine (Ser) and threonine (Thr) residues of specific substrate cellular proteins via the addition of O-GlcNAc group by O-GlcNAc transferase (OGT). Maintenance of normal intracellular levels of O-GlcNAcylation is controlled by OGT and glycoside hydrolase O-GlcNAcase (OGA). Unbalanced O-GlcNAcylation levels have been involved in many diseases, including diabetes, cancer, and neurodegenerative disease. Recent research data reveal that O-GlcNAcylation at histones or non-histone proteins may provide recognition platforms for subsequent protein recruitment and further initiate intracellular biological processes. Here, we review the current understanding of the ‘O-GlcNAc code’ mediated intracellular biological functions of downstream proteins.
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Bernstein, Emily, and Sandra B. Hake. "The nucleosome: a little variation goes a long wayThis paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 84, no. 4 (2006): 505–7. http://dx.doi.org/10.1139/o06-085.
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Changes in the overall structure of chromatin are essential for the proper regulation of cellular processes, including gene activation and silencing, DNA repair, chromosome segregation during mitosis and meiosis, X chromosome inactivation in female mammals, and chromatin compaction during apoptosis. Such alterations of the chromatin template occur through at least 3 interrelated mechanisms: post-translational modifications of histones, ATP-dependent chromatin remodeling, and the incorporation (or replacement) of specialized histone variants into chromatin. Of these mechanisms, the exchange of variants into and out of chromatin is the least well understood. However, the exchange of conventional histones for variant histones has distinct and profound consequences within the cell. This review focuses on the growing number of mammalian histone variants, their particular biological functions and unique features, and how they may affect the structure of the nucleosome. We propose that a given nucleosome might not consist of heterotypic variants, but rather, that only specific histone variants come together to form a homotypic nucleosome, a hypothesis that we refer to as the nucleosome code. Such nucleosomes might in turn participate in marking specific chromatin domains that may contribute to epigenetic inheritance.
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Sarg, Bettina, Rita Lopez, Herbert Lindner, Inma Ponte, Pedro Suau, and Alicia Roque. "Identification of novel post-translational modifications in linker histones from chicken erythrocytes." Journal of Proteomics 113 (January 2015): 162–77. http://dx.doi.org/10.1016/j.jprot.2014.10.004.
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Papanastasiou, Malvina, James Mullahoo, Katherine C. DeRuff, et al. "Chasing Tails: Cathepsin-L Improves Structural Analysis of Histones by HX-MS." Molecular & Cellular Proteomics 18, no. 10 (2019): 2089–98. http://dx.doi.org/10.1074/mcp.ra119.001325.
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The N-terminal regions (tails) of histone proteins are dynamic elements that protrude from the nucleosome and are involved in many aspects of chromatin organization. Their epigenetic role is well-established, and post-translational modifications present on these regions contribute to transcriptional regulation. Considering their biological significance, relatively few structural details have been established for histone tails, mainly because of their inherently disordered nature. Although hydrogen/deuterium exchange mass spectrometry (HX-MS) is well-suited for the analysis of dynamic structures, it has seldom been employed in this context, presumably because of the poor N-terminal coverage provided by pepsin. Inspired from histone-clipping events, we profiled the activity of cathepsin-L under HX-MS quench conditions and characterized its specificity employing the four core histones (H2A, H2B, H3 and H4). Cathepsin-L demonstrated cleavage patterns that were substrate- and pH-dependent. Cathepsin-L generated overlapping N-terminal peptides about 20 amino acids long for H2A, H3, and H4 proving its suitability for the analysis of histone tails dynamics. We developed a comprehensive HX-MS method in combination with pepsin and obtained full sequence coverage for all histones. We employed our method to analyze histones H3 and H4. We observe rapid deuterium exchange of the N-terminal tails and cooperative unfolding (EX1 kinetics) in the histone-fold domains of histone monomers in-solution. Overall, this novel strategy opens new avenues for investigating the dynamic properties of histones that are not apparent from the crystal structures, providing insights into the structural basis of the histone code.
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Pandorf, Clay E., Fadia Haddad, Carola Wright, Paul W. Bodell, and Kenneth M. Baldwin. "Differential epigenetic modifications of histones at the myosin heavy chain genes in fast and slow skeletal muscle fibers and in response to muscle unloading." American Journal of Physiology-Cell Physiology 297, no. 1 (2009): C6—C16. http://dx.doi.org/10.1152/ajpcell.00075.2009.
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Recent advances in chromatin biology have enhanced our understanding of gene regulation. It is now widely appreciated that gene regulation is dependent upon post-translational modifications to the histones which package genes in the nucleus of cells. Active genes are known to be associated with acetylation of histones (H3ac) and trimethylation of lysine 4 in histone H3 (H3K4me3). Using chromatin immunoprecipitation (ChIP), we examined histone modifications at the myosin heavy chain (MHC) genes expressed in fast vs. slow fiber-type skeletal muscle, and in a model of muscle unloading, which results in a shift to fast MHC gene expression in slow muscles. Both H3ac and H3K4me3 varied directly with the transcriptional activity of the MHC genes in fast fiber-type plantaris and slow fiber-type soleus. During MHC transitions with muscle unloading, histone H3 at the type I MHC becomes de-acetylated in correspondence with down-regulation of that gene, while upregulation of the fast type IIx and IIb MHCs occurs in conjunction with enhanced H3ac in those MHCs. Enrichment of H3K4me3 is also increased at the type IIx and IIb MHCs when these genes are induced with muscle unloading. Downregulation of IIa MHC, however, was not associated with corresponding loss of H3ac or H3K4me3. These observations demonstrate the feasibility of using the ChIP assay to understand the native chromatin environment in adult skeletal muscle, and also suggest that the transcriptional state of types I, IIx and IIb MHC genes are sensitive to histone modifications both in different muscle fiber-types and in response to altered loading states.
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Ianniello, Zaira, and Alessandro Fatica. "N6-Methyladenosine Role in Acute Myeloid Leukaemia." International Journal of Molecular Sciences 19, no. 8 (2018): 2345. http://dx.doi.org/10.3390/ijms19082345.
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We are currently assisting in the explosion of epitranscriptomics, which studies the functional role of chemical modifications into RNA molecules. Among more than 100 RNA modifications, the N6-methyladenosine (m6A), in particular, has attracted the interest of researchers all around the world. m6A is the most abundant internal chemical modification in mRNA, and it can control any aspect of mRNA post-transcriptional regulation. m6A is installed by “writers”, removed by “erasers”, and recognized by “readers”; thus, it can be compared to the reversible and dynamic epigenetic modifications in histones and DNA. Given its fundamental role in determining the way mRNAs are expressed, it comes as no surprise that alterations to m6A modifications have a deep impact in cell differentiation, normal development and human diseases. Here, we review the proteins involved in m6A modification in mammals, m6A role in gene expression and its contribution to cancer development. In particular, we will focus on acute myeloid leukaemia (AML), which provides an initial indication of how alteration in m6A modification can disrupt normal cellular differentiation and lead to cancer.
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Lewis, John D., and Juan Ausió. "Protamine-like proteins: evidence for a novel chromatin structure." Biochemistry and Cell Biology 80, no. 3 (2002): 353–61. http://dx.doi.org/10.1139/o02-083.
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Protamine-like (PL) proteins are DNA-condensing proteins that replace somatic-type histones during spermatogenesis. Their composition suggests a function intermediate to that of histones and protamines. Although these proteins have been well characterized at the chemical level in a large number of species, particularly in marine invertebrates, little is known about the specific structures arising from their interaction with DNA. Speculation concerning chromatin structure is complicated by the high degree of heterogeneity in both the number and size of these proteins, which can vary considerably even between closely related species. After careful examination and comparison of the protein sequences available to date for the PL proteins, we propose a model for a novel chromatin structure in the sperm of these organisms that is mediated by somatic-type histones, which are frequently found associated with these proteins. This structure supports the concept that the PL proteins may represent various evolutionary steps between a sperm-specific histone H1 precursor and true protamines. Potential post-translational modifications and the control of PL protein expression and deposition are also discussed.Key words: protamine-like proteins, histones, chromatin structure, sperm, evolution.
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Nair, Divya R., and Elizabeth Bhoj. "3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations." Journal of Clinical and Translational Science 3, s1 (2019): 103. http://dx.doi.org/10.1017/cts.2019.235.
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OBJECTIVES/SPECIFIC AIMS: Histones are nuclear proteins that associate with DNA to facilitate packaging into condensed chromatin. Histones are dynamically decorated with post-translational modifications (PTMs), which regulate such processes as DNA repair, gene expression, mitosis, and meiosis. Histone 3 Family 3 (H3F3) histones (H3.3), encoded by H3F3A and H3F3B, mark active genes, maintain epigenetic memory, and maintain heterochromatin and telomeric integrity. Specific somatic mutations in H3F3A and H3F3B have been strongly associated with pediatric glia and other tumors, but no germline mutations have been reported. The goal of our study was to further understand the functional effects of germline mutations of H3F3A and H3F3B. METHODS/STUDY POPULATION: We analyzed 32 patients bearing de novo germline missense mutations in H3F3A or H3F3B with core phenotypes of progressive neurologic dysfunction and congenital anomalies, but no malignancies. Patient histones were analyzed by quantitative mass spectrometry (qMS). RESULTS/ANTICIPATED RESULTS: qMS results revealed that the mutant histone proteins are present at a concentration similar to that of wild-type H3.3. qMS analysis showed strikingly aberrant PTM patterns that suggested local dysregulation. These patterns are distinct from the dominant negative somatic mutations, which cause more global PTM dysregulation. Patient cells also demonstrated upregulation of the expression of genes related to mitosis and cell division, and had a greater proliferative capacity. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggests that the pathogenic mechanism of germline histone mutations is distinct from that of the published cancer-associated somatic histone mutations, but may converge on control of cell proliferation. Further clarification of the pathophysiology in these patients can elucidate the roles of histones and histone PTMs in human development and non-syndromic neurodegeneration. In addition, it provides a framework for targeted therapy development for this and related progressive neurologic disorders.