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PubMed2004

Linking the epigenetic 'language' of covalent histone modifications to cancer.

Covalent modifications of histones, such as acetylation, methylation, and phosphorylation, and other epigenetic modulations of the chromatin, such as methylation of DNA and ATP-dependent chromatin reorganisation, can play a major part in the multistep process of carcinogenesis, with far-reaching implications for human biology and human health. This review focuses on how aberrant covalent histone modifications may contribute to the development of a variety of human cancers, and discusses the recent findings with regard to potential therapies.

Acetylation↗
PubMed2005

Single-nucleosome mapping of histone modifications in S. cerevisiae.

Covalent modification of histone proteins plays a role in virtually every process on eukaryotic DNA, from transcription to DNA repair. Many different residues can be covalently modified, and it has been suggested that these modifications occur in a great number of independent, meaningful combinations. Published low-resolution microarray studies on the combinatorial complexity of histone modification patterns suffer from confounding effects caused by the averaging of modification levels over multiple nucleosomes. To overcome this problem, we used a high-resolution tiled microarray with single-nucleosome resolution to investigate the occurrence of combinations of 12 histone modifications on thousands of nucleosomes in actively growing S. cerevisiae. We found that histone modifications do not occur independently; there are roughly two groups of co-occurring modifications. One group of lysine acetylations shows a sharply defined domain of two hypo-acetylated nucleosomes, adjacent to the transcriptional start site, whose occurrence does not correlate with transcription levels. The other group consists of modifications occurring in gradients through the coding regions of genes in a pattern associated with transcription. We found no evidence for a deterministic code of many discrete states, but instead we saw blended, continuous patterns that distinguish nucleosomes at one location (e.g., promoter nucleosomes) from those at another location (e.g., over the 3' ends of coding regions). These results are consistent with the idea of a simple, redundant histone code, in which multiple modifications share the same role.

Chromatin Immunoprecipitation↗
PubMed2003

A WW domain-binding motif within the activation domain of the hematopoietic transcription factor NF-E2 is essential for establishment of a tissue-specific histone modification pattern.

Histone H3 methylated at lysine 4 (H3-meK4) co-localizes with hyperacetylated histones H3 and H4 in transcriptionally active chromatin, but mechanisms that establish H3-meK4 are poorly understood. Previously, we showed that the hematopoietic-specific activator NF-E2, which is required for beta-globin transcription in erythroleukemia cells, induces histone H3 hyperacetylation and H3-meK4 at the adult beta-globin genes (betamajor and betaminor). Chromatin immunoprecipitation analysis indicated that NF-E2 occupies hypersensitive site two (HS2) of the beta-globin locus control region. The mechanism of NF-E2-mediated chromatin modification was investigated by complementation analysis in NF-E2-null CB3 erythroleukemia cells. The activation domain of the hematopoietic-specific subunit of NF-E2 (p45/NF-E2) contains two WW domain-binding motifs (PXY-1 and PXY-2). PXY-1 is required for activation of beta-globin transcription. Here, we determined which step in NF-E2-dependent transactivation is PXY-1-dependent. A p45/NF-E2 mutant lacking 42 amino acids of the activation domain, including both PXY motifs, and a mutant lacking only PXY-1 were impaired in inducing histone H3 hyperacetylation, H3-meK4, and RNA polymerase II recruitment. The PXY motifs were not required for transactivation in the context of a GAL4 DNA-binding domain fusion to p45/NF-E2 in transient transfection assays. As the PXY-1 mutant occupied HS2 normally, the chromatin modification defect occurred post-DNA binding. PXY-1 was not required for recruitment of the histone acetyltransferases cAMP-responsive element-binding protein-binding protein (CBP) and p300 to HS2. These results indicate that PXY-1 confers chromatin-specific transcriptional activation via interaction with a co-regulator distinct from CBP/p300 or by regulating CBP/p300 function.

Acetylation↗
PubMed2006

Genome-wide patterns of histone modifications in yeast.

Post-translational histone modifications and histone variants generate complexity in chromatin to enable the many functions of the chromosome. Recent studies have mapped histone modifications across the Saccharomyces cerevisiae genome. These experiments describe how combinations of modified and unmodified states relate to each other and particularly to chromosomal landmarks that include heterochromatin, subtelomeric chromatin, centromeres, origins of replication, promoters and coding regions. Such patterns might be important for the regulation of heterochromatin-mediated silencing, chromosome segregation, DNA replication and gene expression.

Chromosomes, Fungal↗
PubMed1980

Intracellular forms of simian virus 40 nucleoprotein complexes. III. Study of histone modifications.

The modification patterns of histones present in various forms of intracellular simian virus 40 nucleoprotein complexes were analyzed by acetic acid-urea-polyacrylamide gel electrophoresis. The results showed that different viral nucleoprotein complexes contain different histone patterns. Simian virus 40 chromatin, which contains the activities for the synthesis of viral RNA and DNA, exhibits a histone modification pattern similar to that of the host chromatin. However, virion assembly intermediates and mature virions contain highly modified histones. Pulse-chase experiments with [3H]lysine showed that the newly incorporated histones in the virion assembly intermediates were already highly modified. The majority of in vivo acetylation activity of histones occurred on the 70S simian virus 40 chromatin as analyzed by pulse-labeling with [3H]acetate. These results and our previous analysis of the virion assembly pathway suggest that three stages are involved in the packaging of simian virus 40 chromatin into the mature virion: (i) modification of histones, (ii) accumulation of capsid protein around the chromatin with highly modified histones, and (iii) organization of capsid proteins into salt-resistant shells. The role of histone modification in virion assembly is discussed.

Acetylation↗
PubMed2004

The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.

The covalent modification of nucleosomal histones has emerged as a major determinant of chromatin structure and gene activity. To understand the interplay between various histone modifications, including acetylation and methylation, we performed a genome-wide chromatin structure analysis in a higher eukaryote. We found a binary pattern of histone modifications among euchromatic genes, with active genes being hyperacetylated for H3 and H4 and hypermethylated at Lys 4 and Lys 79 of H3, and inactive genes being hypomethylated and deacetylated at the same residues. Furthermore, the degree of modification correlates with the level of transcription, and modifications are largely restricted to transcribed regions, suggesting that their regulation is tightly linked to polymerase activity.

Acetylation↗
PubMed2005

Plasticity of histone modifications across the invertebrate to vertebrate transition: histone H3 lysine 4 trimethylation in heterochromatin.

Histone posttranslational modifications mediate establishment of structurally and functionally distinct chromatin compartments of eukaryotic nuclei. The association of different histone modifications with euchromatic and heterochromatic compartments is relatively conserved in highly divergent model organisms such as Drosophila and mammals. However, some differences between these model systems have been uncovered while limited data are available from organisms nearer the invertebrate-vertebrate transition. We identified a chromatin compartment in both diploid and endocycling cells of the urochordate, Oikopleura dioica, enriched in heterochromatic histone modifications and DNA methylation. Surprisingly, this compartment also contained high levels of histone H3 trimethylated at lysine 4 (H3 Me(3)K4), a modification thus far associated with actively transcribed sequences. Although in Drosophila and mouse cells, H3 Me(3)K4 was prevalently associated with euchromatin, we also detected it in their pericentromeric heterochromatin. We further showed that H3 Me(3)K4 abundance was not necessarily proportional to local levels of transcriptional activity in either euchromatin or heterochromatin. Our data indicate greater plasticity across evolution in the association of histone lysine methylation with functionally distinct chromatin domains than previously thought and suggest that H3 Me(3)K4 participates in additional processes beyond marking transcriptionally active chromatin.

Animals↗
PubMed2006

[Histone modification and regulation of chromatin function].

Nucleosomes play two main roles, acting as basal units in DNA compaction and coordinating most processes in chromosomes. The coordination is due to modification of histones, proteins forming nucleosomes. The review briefly describes the nucleosome structure and major modifications of histones and considers the role of such modifications in transcriptional suppression and activation.

Acetylation↗
PubMed2003

Histone modifications: an assembly line for active chromatin?

Histone modifications play a major role in the control of genes in their natural chromatin context. A detailed, time-resolved analysis of histone modifications during gene activation has now revealed the order of appearance of particular histone modifications on a promoter during regulatory processes.

Animals↗
PubMed2005

Structure and activity of enzymes that remove histone modifications.

The post-translational modification of histones plays an important role in chromatin regulation, a process that insures the fidelity of gene expression and other DNA transactions. Equally important as the enzymes that generate these modifications are the enzymes that remove them. Recent studies have identified some of the enzymes that remove histone modifications and have characterized their activities. In addition, structural and biochemical studies of these enzymes have focused on the histone lysine deacetylases HDAC8 and sirtuins, and on the arginine and lysine demethylases PAD and BHC110/LSD1, respectively. These new findings may be used as a context to present new information that contributes to our understanding of chromatin regulation, and to pose remaining questions pertaining to the activities of these enzymes and the roles they play in chromatin regulation.

Animals↗
PubMed2005

Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications.

PRMT1 is a histone methyltransferase that methylates Arg3 on histone H4. When we used siRNA to knock down PRMT1 in an erythroid cell line, it resulted in nearly complete loss of H4 Arg3 methylation across the chicken beta-globin domain, which we use as a model system for studying the relationship of gene activity to histone modification. We observed furthermore a domain-wide loss of histone acetylation on both histones H3 and H4, as well as an increase in H3 Lys9 and Lys27 methylation, both marks associated with inactive chromatin. To determine whether the effect on acetylation was directly related to the loss of H4 Arg3 methylation, we performed an in vitro acetylation reaction on chromatin isolated from PRMT1-depleted cells. We found that nucleosomes purified from these cells, and depleted in methylation at Arg3, are readily acetylated by nuclear extracts from the same cells, if and only if the nucleosomes are incubated with PRMT1 beforehand. Thus, methylation of histones by PRMT1 was sufficient to permit subsequent acetylation. Consistent with earlier reports of experiments in vitro, H4 Arg3 methylation by PRMT1 appears to be essential in vivo for the establishment or maintenance of a wide range of "active" chromatin modifications.

Acetylation↗
PubMed2003

Histone modifications in Arabidopsis- high methylation of H3 lysine 9 is dispensable for constitutive heterochromatin.

N-terminal modifications of nucleosomal core histones are involved in gene regulation, DNA repair and recombination as well as in chromatin modeling. The degree of individual histone modifications may vary between specific chromatin domains and throughout the cell cycle. We have studied the nuclear patterns of histone H3 and H4 acetylation and of H3 methylation in Arabidopsis. A replication-linked increase of acetylation only occurred at H4 lysine 16 (not for lysines 5 and 12) and at H3 lysine 18. The last was not observed in other plants. Strong methylation at H3 lysine 4 was restricted to euchromatin, while strong methylation at H3 lysine 9 occurred preferentially in heterochromatic chromocenters of Arabidopsis nuclei. Chromocenter appearance, DNA methylation and histone modification patterns were similar in nuclei of wild-type and kryptonite mutant (which lacks H3 lysine 9-specific histone methyltransferase), except that methylation at H3 lysine 9 in heterochromatic chromocenters was reduced to the same low level as in euchromatin. Thus, a high level of H3methylK9 is apparently not necessary to maintain chromocenter structure and does not prevent methylation of H3 lysine 4 within Arabidopsis chromocenters.

Arabidopsis↗
PubMed2025

Multiomics Reveal Associations Between CpG Methylation, Histone Modifications and Transcription in a Species That has Lost DNMT3, the Colorado Potato Beetle.

Insects display exceptional phenotypic plasticity, which can be mediated by epigenetic modifications, including CpG methylation and histone modifications. In vertebrates, both are interlinked and CpG methylation is associated with gene repression. However, little is known about these regulatory systems in invertebrates, where CpG methylation is mainly restricted to gene bodies of transcriptionally active genes. A widely conserved mechanism involves the co-transcriptional deposition of H3K36 trimethylation and the targeted methylation of unmethylated CpGs by the de novo DNA methyltransferase DNMT3. However, DNMT3 has been lost multiple times in invertebrate lineages raising the question of how the links between CpG methylation, histone modifications and gene expression are affected by its loss. Here, we report the epigenetic landscape of Leptinotarsa decemlineata, a beetle species that has lost DNMT3 but retained CpG methylation. We combine RNA-seq, enzymatic methyl-seq and CUT&Tag to study gene expression, CpG methylation and patterns of H3K36me3 and H3K27ac histone modifications on a genome-wide scale. Despite the loss of DNMT3, H3K36me3 mirrors CpG methylation patterns. Together, they give rise to signature profiles for expressed and not expressed genes. H3K27ac patterns show a prominent peak at the transcription start site that is predictive of expressed genes irrespective of their methylation status. Our study provides new insights into the evolutionary flexibility of epigenetic modification systems that urge caution when generalizing across species.

Animals↗
PubMed1999

Histone modification governs the cell cycle regulation of a replication-independent chromatin assembly pathway in Saccharomyces cerevisiae.

We describe a replication-independent, cell cycle-regulated chromatin assembly pathway in budding yeast. The activity of this pathway is low in S phase extracts but is very high in G2, M, and G1 cell extracts, with peak activity in late M/early G1. The cell cycle regulation of this pathway requires a specific pattern of posttranslational modification of histones H3 and/or H4, which is distinct for H3/H4 present in S phase versus M and G1 phase cell extracts. Histone H3/H4 modification is therefore important for the reciprocal control of replication-dependent and -independent chromatin assembly pathways during the cell cycle.

Cell Cycle↗
PubMed1978

The effect of sodium butyrate on histone modification.

The hyperacetylation of histones due to treatment of cultured cells with sodium butyrate has been studied. The hyperacetylation is due to inhibition of histone deacetylase. Other short chain fatty acids including acetic, isobutyric and propionic acid also produce increased modification. Histone H4 already deposited on the chromosome can be rapidly acetylated to the extent of about 70%. That 80% of histone H4 is acetylated after a 24 hr exposure to butyrate is due to the fact that incoming H4 histone is 100% acetylated and does not return to the parental unmodified form in the presence of butyrate.

Acetates↗
PubMed1999

Control of histone modifications.

A role for histone modifications in transcription processes and the remodeling of chromatin structure has been established. This review highlights the recent advances made in studies on histone acetyltransferases, histone deacetylases, histone kinases, and protein phosphatases, as well as their roles in transcriptional activation and repression. Coactivators with histone acetyltransferase activity stimulate transcription, whereas corepressors with histone deacetylase activity repress transcription. Families of histone acetyltransferases and deacetylases have been identified. We have learned that their substrates are not limited to histones but also include transcription factors and architectural proteins. Studies on the composition of multiprotein complexes with histone acetyltransferase or histone deacetylase have revealed mechanisms by which these complexes are recruited to specific genomic sites that are transcriptionally active, silenced, or being repaired. A new and exciting development, presented in this review, is the role of signal transduction pathways in the phosphorylation of histone H3 and the expression of immediate-early genes. J. Cell. Biochem. Suppls. 32/33:141-148, 1999.

Acetylation↗
PubMed2004

Regulation of transcription of the steroidogenic acute regulatory protein (StAR) gene: temporal and spatial changes in transcription factor binding and histone modification.

We examined the binding of transcription factors and histone modifications associated with induction of expression of the steroidogenic acute regulatory protein (StAR) gene in MA-10 cells using a quantitative chromatin immunoprecipitation (ChIP) assay. GATA-4, SF-1/Ad4BP, and cyclic AMP response element binding protein binding protein (CBP) bind rapidly to the StAR proximal promoter, but in different patterns following 8-Br-cAMP stimulation. Concomitantly, histone modifications occur in a spatial and temporal sequence including increased association of acetylated histone H3 with the proximal promoter region, increased association of dimethylated lysine 4 histone H3 with exonic sequences, a modification that marks actively transcribed regions, and reduced association of a marker linked to gene silencing (lysine 9 dimethylated histone H3). Our findings demonstrate that transcription factors and coactivators are rapidly associated with the StAR proximal promoter, that the patterns of binding differ which has implications for postulated direct interactions among these factors, and that multiple histone modifications are demonstrable in a spatially- and temporally-specific pattern along the StAR gene. These observations suggest that a combinatorial code of transcription factors including reciprocal changes in histone modifications associated with active transcription and gene silencing control StAR gene expression.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins.

BACKGROUND: In mammals, there is evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with modification complexes that can deacetylate and/or methylate nucleosomes in the proximity of methylated DNA. We examined this idea for the X chromosome by studying histone modifications on the X chromosome in normal cells and in cells from patients with ICF syndrome (Immune deficiency, Centromeric region instability, and Facial anomalies syndrome). In normal cells the inactive X has characteristic silencing type histone modification patterns and the CpG islands of genes subject to X inactivation are hypermethylated. In ICF cells, however, genes subject to X inactivation are hypomethylated on the inactive X due to mutations in the DNA methyltransferase (DNMT3B) genes. Therefore, if DNA methylation is upstream of histone modification, the histones on the inactive X in ICF cells should not be modified to a silent form. In addition, we determined whether a specific methyl-CpG binding protein, MeCP2, is necessary for the inactive X histone modification pattern by studying Rett syndrome cells which are deficient in MeCP2 function. RESULTS: 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. CONCLUSIONS: 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.

Cells, Cultured↗