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A tale of histone modifications
Patrick A Grant
Genome Biology , 2001, DOI: 10.1186/gb-2001-2-4-reviews0003
Abstract: In eukaryotes, genomic DNA is packaged with histone proteins into chromatin, compacting DNA some 10,000-fold. Such condensation of DNA provides a considerable obstacle to the nuclear machinery that drives processes such as replication, transcription or DNA repair. Importantly, the structure of chromatin dynamically changes, permitting localized decondensation and remodeling that facilitates the progress of nuclear machinery. An emerging theme in the field of chromatin research has been the significant role that posttranslational modifications of histones play in regulating nuclear function. Over the past few years, considerable progress has been made into the identification of the enzymatic machines that modify these proteins, and this review is devoted to our current understanding of the array of core histone modifications and the factors that regulate them.The basic repeating unit of chromatin is the nucleosome, typically composed of an octamer of the four core histones H2A, H2B, H3 and H4 and 146 basepairs of DNA wrapped around the histones [1]. Each core histone is composed of a structured domain and an unstructured amino-terminal 'tail' of 25-40 residues. This unstructured tail extends through the DNA gyres and into the space surrounding the nucleosomes. Histone tails provide sites for a variety of posttranslational modifications, including acetylation, phosphorylation and methylation. It is becoming increasingly apparent that such modifications of histone tails determine the interactions of histones with other proteins, which may in turn also regulate chromatin structure [2]. Identifying the multitude of histone modifications, the enzymes that generate them and the nuclear response to any given pattern of alterations poses a fascinating challenge.The acetylation and deacetylation of the ε-amino groups of conserved lysine residues present in histone tails has long been linked to transcriptional activity [3] and has been the most intensively studied histone modi
Ontogenetic Survey of Histone Modifications in an Annelid  [PDF]
Glenys Gibson,Corban Hart,Robyn Pierce,Vett Lloyd
Genetics Research International , 2012, DOI: 10.1155/2012/392903
Abstract: Histone modifications are widely recognized for their fundamental importance in regulating gene expression in embryonic development in a wide range of eukaryotes, but they have received relatively little attention in the development of marine invertebrates. We surveyed histone modifications throughout the development of a marine annelid, Polydora cornuta, to determine if modifications could be detected immunohistochemically and if there were characteristic changes in modifications throughout ontogeny (surveyed at representative stages from oocyte to adult). We found a common time of onset for three histone modifications in early cleavage (H3K14ac, H3K9me, and H3K4me2), some differences in the distribution of modifications among germ layers, differences in epifluorescence intensity in specific cell lineages suggesting that hyperacetylation (H3K14ac) and hypermethylation (H3K9me) occur during differentiation, and an overall decrease in the distribution of modifications from larvae to adults. Although preliminary, these results suggest that histone modifications are involved in activating early development and differentiation in a marine invertebrate. 1. Introduction One of the central questions in biology is how differences in gene expression during development lead to the generation of form. Epigenetic mechanisms such as histone modifications activate or silence gene expression and thereby provide rapid, reversible mechanisms that regulate gene expression in embryonic development. The importance of histone modifications in development has been extensively studied in model systems. As this approach is gradually extended to nonmodel species, histone modifications are being discovered as mechanisms that are highly conserved in a wide variety of eukaryotes and critically important in regulating fundamental developmental processes, including meiosis [1], cell differentiation [2], organ development in plants [3], sexual and asexual reproduction in fungi [4], genomic imprinting in plants and insects [5], and X-inactivation in mammals [6]. Despite the clearly established importance of histone modifications in the development of many eukaryotes, they have received almost no attention in the development of benthic marine invertebrates. Benthic marine invertebrates represent an exciting group for epigenetic research as they not only are morphologically diverse as adults, but their larvae are morphologically and behaviorally distinct from adults and form the basis for an impressive diversity of life-history patterns. Our objectives are to determine if histone
Enhanced top-down characterization of histone post-translational modifications
Zhixin Tian, Nikola Toli?, Rui Zhao, Ronald J Moore, Shawna M Hengel, Errol W Robinson, David L Stenoien, Si Wu, Richard D Smith, Ljiljana Pa?a-Toli?
Genome Biology , 2012, DOI: 10.1186/gb-2012-13-10-r86
Abstract: Histones are important chromatin proteins that act as spools to package and order DNA into structural and manageable chromosomes. Core histones are modified by multiple post-translational modifications (PTMs) such as lysine acetylation, lysine or arginine methylation, and serine or threonine phosphorylation, among others. These PTMs generate a 'histone code' [1] that is implicated in chromatin-related cellular processes [2] including transcription [3], replication [4], repair [5], and alternative splicing [6].Although core histones comprise only four families (H4, H2B, H2A, and H3), each family has thousands of potential isoforms generated by different combinations of PTMs and protein sequence variation. Traditional antibody-based methods target specific isoforms, typically analyzing one PTM at a time, which makes it virtually impossible to measure combinatorial modifications occurring within the same histone molecule. Recently, high-throughput bottom-up [7] and middle-down [8] proteomic methods demonstrated potential for global characterization of PTMs on histone tails. However, these methods are ill-suited for characterizing multiple PTMs dispersed along the entire protein sequence that have been previously discovered to have significant participation in chromatin regulation [2,9-11].Top-down proteomic and high-throughput approaches are clearly required to identify and quantify the modulation of multiple intra-molecular histone modifications that synergistically regulate histone functions. Recently, a global top-down study demonstrated the feasibility of intact protein analysis for this purpose by identifying more than 300 histone isoforms using extensive fractionation and customized bioinformatics for global proteome characterization [12]. In histone-focused studies, top-down approaches using an offline two-dimensional liquid chromatography (2D LC) separation and Fourier transform mass spectrometry (FTMS) characterized 34 H4 isoforms from approximately 150 μg of
Determination of enriched histone modifications in non-genic portions of the human genome
Jeffrey A Rosenfeld, Zhibin Wang, Dustin E Schones, Keji Zhao, Rob DeSalle, Michael Q Zhang
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-143
Abstract: We have extended the analysis of histone modifications to gene deserts, pericentromeres and subtelomeres. Using data from human CD4+ T cells, we have found that each of these non-genic regions has a particular profile of histone modifications that distinguish it from the other non-coding regions. Different methylation states of H4K20, H3K9 and H3K27 were found to be enriched in each region relative to the other regions. These findings indicate that non-genic regions of the genome are variable with respect to histone modification patterns, rather than being monolithic. We furthermore used consensus sequences for unassembled centromeres and telomeres to identify the significant histone modifications in these regions. Finally, we compared the modification patterns in non-genic regions to those at silent genes and genes with higher levels of expression. For all tested methylations with the exception of H3K27me3, the enrichment level of each modification state for silent genes is between that of non-genic regions and expressed genes. For H3K27me3, the highest levels are found in silent genes.In addition to the histone modification pattern difference between euchromatin and heterochromatin regions, as is illustrated by the enrichment of H3K9me2/3 in non-genic regions while H3K9me1 is enriched at active genes; the chromatin modifications within non-genic (heterochromatin-like) regions (e.g. subtelomeres, pericentromeres and gene deserts) are also quite different.The chromatin state and transcription level of a chromosomal region has been found to be related to modifications of histones [1,2] as well as DNA [3,4]. The fundamental structural unit of chromatin is the nucleosome, which is formed by wrapping DNA around a histone octamer consisting of two copies each of four core histone proteins (H2A, H2B, H3, and H4). The tails of these histones can be modified in a variety of ways that relate to chromatin condensation and gene expression[2]. Different histone residues can be
Application of Celluspots peptide arrays for the analysis of the binding specificity of epigenetic reading domains to modified histone tails
Ina Bock, Srikanth Kudithipudi, Raluca Tamas, Goran Kungulovski, Arunkumar Dhayalan, Albert Jeltsch
BMC Biochemistry , 2011, DOI: 10.1186/1471-2091-12-48
Abstract: We describe the application of Celluspots peptide arrays which contain 384 histone peptides carrying 59 post translational modifications in different combinations as an inexpensive, reliable and fast method for initial screening for specific interactions of reading domains with modified histone peptides. To validate the method, we tested the binding specificities of seven known epigenetic reading domains on Celluspots peptide arrays, viz. the HP1? and MPP8 Chromo domains, JMJD2A and 53BP1 Tudor domains, Dnmt3a PWWP domain, Rag2 PHD domain and BRD2 Bromo domain. In general, the binding results agreed with literature data with respect to the primary specificity of the reading domains, but in almost all cases we obtained additional new information concerning the influence of secondary modifications surrounding the target modification.We conclude that Celluspots peptide arrays are powerful screening tools for studying the specificity of putative reading domains binding to modified histone peptides.Epigenetic signals include the methylation of DNA, the post-translational modification (PTM) of the N-terminal histone tails and non-coding RNAs. In eukaryotes, these epigenetic marks are involved in the regulation of gene expression and chromatin state. The most studied histone tail modifications are acetylation of Lys, methylation of Lys or Arg leading to mono-, di- (symmetric or asymmetric in the case of Arg) or trimethylation in the case of Lys and phosphorylation at Ser or Thr [1-4]. These PTMs are recognized and bound by specific reading domains which mediate most of the biological functions of histone tail PTMs [5,6]. Up to date more than 100 different PTMs have been discovered in histone tails, with many of them known to have distinct and important roles in the regulation of gene expression, DNA repair and replication, chromatin biology and the cell cycle. While histone lysine acetylation has a general activating role on transcription, histone lysine methylation can fu
Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins
Stanley M Gartler, Kartik R Varadarajan, Ping Luo, Theresa K Canfield, Jeff Traynor, Uta Francke, R Scott Hansen
BMC Biology , 2004, DOI: 10.1186/1741-7007-2-21
Abstract: We show here that the inactive X in ICF cells, which appears to be hypomethylated at all CpG islands, exhibits normal histone modification patterns. In addition, in Rett cells with no functional MeCP2 methyl-CpG binding protein, the inactive X also exhibits normal histone modification patterns.These data suggest that DNA methylation and the associated methyl-DNA binding proteins may not play a critical role in determining histone modification patterns on the mammalian inactive X chromosome at the sites analyzed.Although it has been known for some time that histone modifications play a role in gene expression [1], it is only in the last several years that the details of these modifications have been more fully described. Acetylation and methylation of histone tails, for example, exhibit characteristic patterns for expressed and repressed genes in all eukaryotes studied [2]. This generality of histone modification and gene expression holds for eukaryotes with and without DNA methylation, indicating that DNA methylation is not required for histone modification. In organisms with DNA methylation, however, interactions between histone modification and DNA methylation do appear to exist.In Neurospora, histone methylation appears to determine DNA methylation patterns [3,4]. In Arabidopsis, non-CpG DNA methylation also appears to be determined by histone methyltransferases, whereas CpG methylation does not [5,6]. In mammals, there is considerable evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with histone deacetylases [7-11]. Mutations in the MeCP2 methyl-DNA binding protein, which are the cause of most Rett syndrome cases [12], support this model, because human male and female cells with MECP2 mutations exhibit histone hyperacetylation [10]. Histone hyperacetylation was also observed in mice with Mecp2 mutations [13]. Thus, DNA methylation is upstream of histone modification in this model o
Modeling Exon Expression Using Histone Modifications  [PDF]
Shijia Zhu, Guohua Wang, Bo Liu, Yadong Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067448
Abstract: Histones undergo numerous covalent modifications that play important roles in regulating gene expression. Previous investigations have focused on the effects of histone modifications on gene promoters, whereas efforts to unravel their effects on transcribed regions have lagged behind. To elucidate the effects of histone modification on transcribed regions, we constructed a quantitative model, which we suggest can predict the variation of gene expression more faithfully than the model constructed on promoters. Moreover, motivated by the fact that exon spicing is functionally coupled to transcription, we also devised a quantitative model to predict alternative exon expression using histone modifications on exons. This model was found to be general across different exon types and even cell types. Furthermore, an interaction network linking histone modifications to alternative exon expression was constructed using partial correlations. The network indicated that gene expression and specific histone modifications (H3K36me3 and H4K20me1) could directly influence the exon expression, while other modifications could act in an additive way to account for the stability and robustness. In addition, our results suggest that combinations of histone modifications contribute to exon splicing in a redundant and cumulative fashion. To conclude, this study provides a better understanding of the effects of histone modifications on gene transcribed regions.
Role of Histone Tails in Structural Stability of the Nucleosome  [PDF]
Mithun Biswas,Karine Voltz,Jeremy C. Smith,J?rg Langowski
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1002279
Abstract: Histone tails play an important role in nucleosome structure and dynamics. Here we investigate the effect of truncation of histone tails H3, H4, H2A and H2B on nucleosome structure with 100 ns all-atom molecular dynamics simulations. Tail domains of H3 and H2B show propensity of -helics formation during the intact nucleosome simulation. On truncation of H4 or H2B tails no structural change occurs in histones. However, H3 or H2A tail truncation results in structural alterations in the histone core domain, and in both the cases the structural change occurs in the H2A3 domain. We also find that the contacts between the histone H2A C terminal docking domain and surrounding residues are destabilized upon H3 tail truncation. The relation between the present observations and corresponding experiments is discussed.
Modeling the Dynamics of Bivalent Histone Modifications  [PDF]
Wai Lim Ku, Michelle Girvan, Guo-Cheng Yuan, Francesco Sorrentino, Edward Ott
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077944
Abstract: Epigenetic modifications to histones may promote either activation or repression of the transcription of nearby genes. Recent experimental studies show that the promoters of many lineage-control genes in stem cells have “bivalent domains” in which the nucleosomes contain both active (H3K4me3) and repressive (H3K27me3) marks. It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear. Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns. We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states.
Modeling the dynamics of bivalent histone modifications  [PDF]
Wai Lim Ku,Michelle Girvan,Guo-Cheng Yuan,Francesco Sorrentino,Edward Ott
Quantitative Biology , 2013,
Abstract: Epigenetic modifications to histones may promote either activation or repression of the transcription of nearby genes. Recent experimental studies show that the promoters of many lineage-control genes in stem cells have "bivalent domains" in which the nucleosomes contain both active (H3K4me3) and repressive (H3K27me3) marks. It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear. Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns. We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states.
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