Synthesis and modification of the histones during the decidual cell reaction in the mouse uterus.
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Acetylation↗
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Modifications of the histone N-terminal domains. Evidence for an "epigenetic code"?
A multicellular organism is made up of a variety of different cell types and tissues. This organization is accomplished by a well-concerted action of different regulatory molecules, which--in a very hierarchical manner--influence the expression of certain cell-specific genes. Many of those regulators are transcription factors, which directly influence the expression of the controlled gene by binding to a specific DNA sequence within its promoter or enhancer region. This binding then leads to an enhancement or a decrease in the rate of transcription of that particular gene and eventually regulates the production of the corresponding polypeptide. One major obstacle to the binding of these transcription factors is the fact that DNA is not readily accessible in the eukaryotic nucleus. It is associated with a class of very basic proteins called histones. This complex of histones and DNA is called chromatin.
Animals↗
A mechanistic approach to anticancer therapy: targeting the cell cycle with histone deacetylase inhibitors.
The activity of genes encoded by the highly-condensed DNA in cellular nuclei must be precisely regulated. Regulation of the accessibility of gene promoters to transcription complexes is one level of gene regulation and is influenced by histone tail modifications such as acetylation, methylation, and phosphorylation. Acetylation is a reversible modification catalyzed by histone acetyl transferase (HAT) and histone deacetyltransferase (HDAC) enzymes. Histone deacetylation is associated with transcriptional repression of genes, as the removal of acetyl groups from lysine residues allows for tighter electrostatic interactions between DNA and histones, limiting accessibility of the DNA for transcription. Inhibition of HDAC activity permits histones to remain in an acetylated state, and through the resulting alterations in gene regulation, inhibits cell cycle progression, inhibits differentiation, and in some cases induces apoptosis. Inhibition of proliferation by HDAC inhibitors is characterized by arrest at the G1 or G2/M phases of the cell cycle. Many types of tumor cells then undergo programmed cell death. Exposure to HDAC inhibitors may also allow reactivation of tumor suppressor genes which had been silenced by hypoacetylation during tumorigenesis. HDAC inhibitors from a number of chemical classes have shown promise as anti-cancer agents in animal studies and early clinical trials. The development of HDAC inhibitors which specifically target HDAC isozymes, and more detailed understanding of their anti-neoplastic actions, heralds a new epigenetic antitumor therapeutic strategy.
Animals↗
Tudor, MBT and chromo domains gauge the degree of lysine methylation.
The post-translational modification of histones regulates many cellular processes, including transcription, replication and DNA repair. A large number of combinations of post-translational modifications are possible. This cipher is referred to as the histone code. Many of the enzymes that lay down this code have been identified. However, so far, few code-reading proteins have been identified. Here, we describe a protein-array approach for identifying methyl-specific interacting proteins. We found that not only chromo domains but also tudor and MBT domains bind to methylated peptides from the amino-terminal tails of histones H3 and H4. Binding specificity observed on the protein-domain microarray was corroborated using peptide pull-downs, surface plasma resonance and far western blotting. Thus, our studies expose tudor and MBT domains as new classes of methyl-lysine-binding protein modules, and also demonstrates that protein-domain microarrays are powerful tools for the identification of new domain types that recognize histone modifications.
Histones↗
Nuclear organization of centromeric domains is not perturbed by inhibition of histone deacetylases.
It is well established that modification of lysines in histone molecules correlates with gene expression and chromatin structure. It is not known whether this operates entirely at a local level, e.g. through the recruitment of specific proteins, or whether histone modifications might impact on more long-range aspects of chromatin organization. There is a distinctive organization of chromatin within the nucleus and the chromatin at the nuclear periphery of mammalian cells appears to be hypoacetylated. Previously it had been suggested that inhibition of histone deacetylases by TSA causes a gross remodeling of nuclear structure, specifically the recruitment of centromeric heterochromatin to the nuclear periphery. Here, we have quantified the nuclear organization of histone modifications and the localization of centromeric domains in human cells before and after TSA treatment. TSA alters the nuclear distribution of histone acetylation, but not that of histone methylation. TSA elevates levels of histone acetylation at the nuclear periphery but we see no alteration in the position of centromeric domains in the nuclei of treated cells. We conclude that the distinctive nuclear localization of centromeric domains is independent of histone acetylation.
Acetylation↗
Post-translational modifications of Trypanosoma cruzi histone H4.
Histone tails provide sites for a variety of post-translational modifications implicated in the control of gene expression and chromatin assembly. As both histones and control of gene expression in trypanosomes are highly divergent compared to most eukaryotes, post-translational modifications of Trypanosoma cruzi histones were investigated. After in vivo incubation of live parasites with radiolabeled precursors, histone H4 mainly incorporates [(3)H]-acetyl, and to a lesser extent [(3)H]-methyl residues. In contrast, histone H3 preferentially incorporates [(3)H]-methyl residues. The modifications of histone H4 were further characterized by mass spectrometry. MALDI-TOF-TOF-MS analysis revealed that peptides from histone H4 amino-terminus, obtained by either endoproteinase Glu-C or endoproteinase Arg-C digestion, contain isoforms with 14 and 42Da additions, suggesting the presence of simultaneous acetylations and/or methylations. Tandem mass spectrometry analysis demonstrated that the N-terminal alanine is methylated, and lysine residues at positions 4, 10, 14 and 57 are acetylated; lysine at position 18 is mono-methylated, while arginine at position 53 is dimethylated. Immunoblotting analyses using specific antibodies raised against synthetic and acetylated peptides of T. cruzi histone H4 indicate that lysine 4 is acetylated in the majority of histone H4, while other acetylations at the N-terminus portion of histone H4 are less abundant.
Acetylation↗
Methylation of histone H3 at Lys4 differs between paternal and maternal chromosomes in Sciara ocellaris germline development.
An outstanding example of programmed chromosome elimination and genomic imprinting is found in sciarid flies (Diptera, Sciaridae), where whole chromosomes of paternal origin are selectively discarded from the genome during development. In early germ cells a single paternal X chromosome is eliminated in embryos of both sexes and in male meiotic cells the whole paternal complement is discarded. In sciarids, differential acetylation of histones H3 and H4 occurs between chromosomes of different parental origin, both in early germ nuclei and in male meiotic cells (Goday and Ruiz, 2002). We here investigated histone methylation modifications between chromosomes in germline cells of Sciara ocellaris. In early germ nuclei, maternal chromosomes show high levels of di- and trimethylated histone H3 at Lys4, whereas this histone modification is not detected in paternal chromosomes. In male meiosis, only the eliminated paternal chromosomes exhibit high levels of di- and trimethylated histones H3 at Lys4 and dimethylated H4 at Lys20. In early germ nuclei, RNA polymerase II associates to maternally-derived chromosomes but lacks phosphorylation of the C-terminal domain on Ser2. We found that histone H3 methylation at Lys4 does not correlate with transcriptional activity in early Sciara germline nuclei. The results support the conclusion that specific covalent chromatin modifications are involved in the imprinted behaviour of germline chromosomes in Sciara.
Acetylation↗
Butyrates and decitabine cooperate to induce histone acetylation and granulocytic maturation of t(8;21) acute myeloid leukemia blasts.
Core histones are proteins organized in octamers, to which DNA is wrapped more or less tightly, depending on their acetylation status. Gene transcription is regulated by a complex series of epigenetic modifications, i.e., histone modification such as methylation and acetylation, events determined by the enzymatic activity of histone methyltransferases, and histone acetyltransferases, respectively, the latter counterbalanced by histone deacetylases (HDAC). Acetylation of histones facilitates destabilization of DNA-nucleosome interaction and renders DNA more accessible to transcription factors. Methylation of different specific lysine residues of histones is differently linked to euchromatin (transcripted DNA) or heterochromatin (silenced DNA). On the other hand, methylation of the promoter regions of some genes by DNA methyltransferases (DNMT) leads to transcriptional silencing and is a common mechanism to regulate gene expression. In normal eukaryotic cells, DNA methylation and histone acetylation are interdependent and maintain equilibrium, allowing temporal expression of genes. In neoplastic cells, this balance is frequently disrupted. In leukemic cells, hypermethylation of CpG islands in the promoter region of genes critical for cell cycle and maturation is frequent, and DNMTs were found to be overexpressed, findings paralleled by evidence of transcriptional repression of downstream genes. Therefore, the combination of HDAC and DNMT inhibitors has been considered to be a possible therapeutic approach to restore normal gene expression in acute myeloid leukemia (AML) and other diseases. Human AML1/ETO Kasumi cells were exposed to the HDAC inhibitor D1 (O-n-butanoil-2,3-O-isopropylidene-alpha-D: -mannofuranoside) and 5-aza-deoxycytidine (decitabine) alone and in combination. Histone acetylation as measured by flow cytometry was increased following treatment with D1 and the combination of D1 and decitabine. Addition of D1 alone or in combination with decitabine also led to inhibition of cell proliferation and induction of apoptosis. Thus, treatment of AML with HDAC inhibitors such as D1 and DNMT inhibitors such as decitabine might have clinical benefit for patients, especially these presenting subtypes of AML, like AML1/ETO, in which the leukemogenic mechanism involves corepressor protein complexes containing HDAC and DNMT.
Antineoplastic Combined Chemotherapy Protocols↗
Global maintenance of histone post-translational modifications during the transition into anoxia in embryos of the annual killifish Austrofundulus limnaeus.
Many organisms have adapted to survive anoxic or hypoxic environments, but the epigenetic responses involved in this successful stress response are not well described in most species. Embryos of the annual killifish Austrofundulus limnaeus have the greatest tolerance to anoxia of all vertebrates, making them a powerful model to study the cellular mechanisms necessary for anoxia tolerance. However, the global histone landscape of this species has never been quantified or explored in relation to stress tolerance. Liquid chromatography-mass spectrometry and a Python bioinformatics workflow were used to identify histones and their post-translational modifications. This pipeline resulted in the detection of 252 unique biologically relevant histone post-translational modifications (hPTMs) (unimod + residue). These PTMs represent 16 types of biologically relevant hPTMs present during both anoxia and normoxia in Wourms' stage 36 embryos. This hPTM library presents an exciting opportunity to study histone modifications across development and in response to environmental stressors. No significant changes in PTM or histone abundance were observed between anoxic and normoxic embryos, suggesting that 24 h of anoxia is not sufficient to induce epigenetic or histone isoform changes at the organismal level. This result is inconsistent with data presented for similar stresses in mammalian cells and thus stabilization of the hPTM landscape may be an adaptation that supports anoxia tolerance.
anoxia↗
Emerging connections between DNA methylation and histone acetylation.
Modifications of both DNA and chromatin can affect gene expression and lead to gene silencing. Evidence of links between DNA methylation and histone hypoacetylation is accumulating. Several proteins that specifically bind to methylated DNA are associated with complexes that include histone deacetylases (HDACs). In addition, DNA methyltransferases of mammals appear to interact with HDACs. Experiments with animal cells have shown that HDACs are responsible for part of the repressive effect of DNA methylation. Evidence was found in Neurospora that protein acetylation can in some cases affect DNA methylation. The available data suggest that the roles of DNA methylation and histone hypoacetylation, and their relationship with each other, can vary, even within an organism. Some open questions in this emerging field that should be answered in the near future are discussed.
Acetylation↗
Maintenance of chromatin states: an open-and-shut case.
The traditional view of chromatin envisions two states: one is 'active' and accessible to nucleases, whereas the other is 'silent' and relatively inaccessible. Recent evidence that combinations of diverse histone tail modifications represent a spectrum of chromatin states challenges this simple view. Here, we examine inter-relationships between chromatin remodeling, histone modification, DNA methylation, RNA interference, and nucleosome assembly activities. We find that the two-state view can accommodate these new findings, and that nucleosome assembly pathways may ultimately maintain euchromatic and heterochromatic states.
Animals↗
The DNA damage checkpoint response requires histone H2B ubiquitination by Rad6-Bre1 and H3 methylation by Dot1.
The cellular response to DNA lesions entails the recruitment of several checkpoint and repair factors to damaged DNA, and chromatin modifications may play a role in this process. Here we show that in Saccharomyces cerevisiae epigenetic modification of histones is required for checkpoint activity in response to a variety of genotoxic stresses. We demonstrate that ubiquitination of histone H2B on lysine 123 by the Rad6-Bre1 complex, is necessary for activation of Rad53 kinase and cell cycle arrest. We found a similar requirement for Dot1-dependent methylation of histone H3. Loss of H3-Lys(79) methylation does not affect Mec1 activation, whereas it renders cells checkpoint-defective by preventing phosphorylation of Rad9. Such results suggest that histone modifications may have a role in checkpoint function by modulating the interactions of Rad9 with chromatin and active Mec1 kinase.
Binding Sites↗
Comprehensive mass spectrometry screening-derived atlas of HDAC inhibitors reveals histone-specific acetylation changes.
Histone deacetylase inhibitors (HDACis) have emerged as valuable therapeutics for cancer and other diseases; however, their effects on histone post-translational modification remain poorly characterized. Here, we applied quantitative mass spectrometry and high-throughput sequencing to systematically profile site-specific changes in histone modifications in response to a panel of HDACis. This platform enabled mapping of histone modification changes across hundreds of sites, including low-abundance histone marks. Furthermore, an integrative analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) data identified genome-wide binding sites for the low-abundance histone modification of H2A.Z acetylation in HeLa and MDA-MB-231 breast cancer cells, highlighting the role of H2A.Z acetylation in regulating gene expression across diverse biological pathways, including specific genes involved in tumor suppressor pathways. Our findings provide a functional resource for identifying and quantifying histone modification changes and transcriptional regulation of histone H2A.Z acetylation following pharmacological perturbation.
Histone Deacetylase Inhibitors↗
Metabolism of histones in avian erythroid cells.
The synthesis and enzymatic modifications of histones by phosphorylation, acetylation, and methylation during erythroid cell maturation have been studied. All newly synthesized histones, H1, H5, H2a, h2b, h3, and H4 undergo phosphorylation; histones H2a, H2b, H3, and H4, are acetylated and histones H3 and H4 are methylated. This type of histone metabolism is common to all dividing cells and therefore may be related to the assembly of histones into chromatin subunits. In the nondividing reticulocytes, the synthesis of histone H5 continues, while all the other histones show negligible incorporation of [3H]amino acids. Furthermore, the reticulocytes show a unique pattern of enzymatic modification: phosphorylation of histone H2b, acetylation of histones H2a, H2b, H3, and H4, and methylation of histones H3 and H4. These "differentiation-linked" modifications are not dependent on histone synthesis, nor related to RNA synthesis, but may be related to the reorganization of chromatin in preparation for genomic inactivation.
Acetates↗
DNA and histone methylation in plants.
Heritable patterns of gene activity and gene silencing arise by the formation and the propagation of specific chromatin states that restrict or permit gene expression. In mammals and in plants, restrictive heterochromatin is associated with the hypermethylation of DNA at CG sites and with the specific modification of histones, such as the methylation of histone H3 at lysine 9 (H3K9(Me)). In addition to CG methylation, plant nuclear DNA packaged in restrictive chromatin is also usually methylated in cytosines outside a CG sequence context. The functional relationship between an unexpectedly complex plant DNA-methylation system and histone modifications that lead to chromatin compaction and gene silencing is under intense scrutiny. The results of recent studies indicate intriguing links between chromatin remodeling, histone methylation, DNA methylation and RNA interference.
Chromatin↗
Chromatin remodeling in somatic cells injected into mature pig oocytes.
We examined the involvement of histone H3 modifications in the chromosome condensation and decondensation of somatic cell nuclei injected into mature pig oocytes. Nuclei of pig granulosa cells were transferred into in vitro matured intact pig oocytes, and histone H3 phosphorylation, acetylation, and methylation were examined by immunostaining with specific antibodies in relation to changes in chromosome morphology. In the condensed chromosomes of pig oocytes at metaphase II, histone H3 was phosphorylated at serine 10 (H3-S10) and serine 28 (H3-S28), and methylated at lysine 9 (H3-K9), but was not acetylated at lysine 9, 14 and 18 (H3-K9, H3-K14 and H3-K18). During the first 2 h after nuclear transfer, a series of events were observed in the somatic nuclei: nuclear membrane disassembly; chromosome condensation to form a metaphase-like configuration; an increase in histone H3 phosphorylation levels (H3-S10 and H3-S28). Next, pig oocytes injected with nuclei of somatic cells were electroactivated and the chromosome morphology of oocytes and somatic cells was examined along with histone modifications. Generally, chromosomes of the somatic cells showed a similar progression of cell cycle stage to that of oocytes, through anaphase II- and telophase II-like stages then formed pronucleus-like structures, although the morphology of the spindles differed from that of oocyte spindles. The chromosomes of somatic cells also showed changes in histone H3 dephosphorylation and reacetylation, similar to oocytes. In contrast, histone H3 methylation (H3-K9) of somatic cell nuclei did not show any significant change after injection and electroactivation of the oocytes. These results suggest that nuclear remodeling including histone H3 phosphorylation and acetylation of injected somatic nuclei took place in the oocytes under regulation by the oocyte cytoplasm.
Acetylation↗
Histone H4 post-translational modifications in chordate mitotic and endoreduplicative cell cycles.
Histone post-translational modifications mark distinct structural and functional chromatin states but little is known of their involvement in the progression of different cell cycle types across phylogeny. We compared temporal and spatial dynamics of histone H4 post-translational modifications during both mitotic and endoreduplicative cycles of the urochordate, Oikopleura dioica, and proliferating mammalian cells. Endocycling cells showed no signs of chromosome condensation or entry into mitosis. They exhibited an evolution of replication patterns indicative of reduced chromatin compartmentalization relative to proliferating mammalian cells. In the latter cells, published cell cycle profiles of histone H4 acetylated at lysine 16 (H4AcK16) or dimethylated at lysine 20 (H4Me2K20) are disputed. Our results, using different, widely used H4AcK16 antibodies, revealed significant antibody-specific discrepancies in spatial and temporal cell cycle regulation of this modification, with repercussions for interpretation of previous immunofluorescence and immunoprecipitation data based on these reagents. On the other hand, three different antibodies to H4Me2K20 revealed similar cell cycle profiles of this modification that were conserved throughout the mitotic cell cycle in urochordate and mammalian cells, with accumulation at mitosis and a decrease during S-phase. H4Me2K20 also cycled in endocycles, indicating that dynamics of this modification are not strictly constrained by the mitotic phase of the cell cycle and suggesting additional roles during G- and S-phase progression. This article contains Supplementary Material available at http://www.mrw.interscience.wiley.com/suppmat/0730-2312/suppmat/2005/95/spada.html.
Acetylation↗
Epigenome changes in active and inactive polycomb-group-controlled regions.
The Polycomb group (PcG) of proteins conveys epigenetic inheritance of repressed transcriptional states. In Drosophila, the Polycomb repressive complex 1 (PRC1) maintains the silent state by inhibiting the transcription machinery and chromatin remodelling at core promoters. Using immunoprecipitation of in vivo formaldehyde-fixed chromatin in phenotypically diverse cultured cell lines, we have mapped PRC1 components, the histone methyl transferase (HMT) Enhancer of zeste (E(z)) and histone H3 modifications in active and inactive PcG-controlled regions. We show that PRC1 components are present in both cases, but at different levels. In particular, active target promoters are nearly devoid of E(z) and Polycomb. Moreover, repressed regions are trimethylated at lysines 9 and 27, suggesting that these histone modifications represent a mark for inactive PcG-controlled regions. These PcG-specific repressive marks are maintained by the action of the E(z) HMT, an enzyme that has an important role not only in establishing but also in maintaining PcG repression.
Animals↗