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PubMed2025

Genome-Wide Profiling of Histone Modifications in Fission Yeast Using CUT&Tag.

Eukaryotic DNA is organized in the nucleus in the form of chromatin. Nucleosomes, the fundamental unit of chromatin, are subject to many posttranslational modifications (PTMs) as well as compositional variations through incorporation of histone variants. These alterations play important roles in regulation of genome structure and activity. Genome-wide profiling of these regulatory features is essential for understanding of genome function. Chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) is a widely used method to assay genome-wide localization in fission yeast but suffers from the requirement for a large amount of input chromatin, antibodies, and a cumbersome experimental pipeline. New methods such as Cleavage Under Targets and Tagmentation (CUT&Tag), which combine the specificity of targeted cleavage and adapter insertion with the sensitivity of next-generation sequencing, enable identification and characterization of various epigenetic marks affording low input requirement as well as more streamlined protocols. However, these approaches have not been adapted for use in fission yeast, Schizosaccharomyces pombe. Here, we describe an adapted CUT&Tag protocol for epigenomic profiling in fission yeast using the heterochromatin-associated histone H3K9 methylation PTM for benchmarking.

Schizosaccharomyces↗
PubMed1984

Histone modification in early and late Drosophila embryos.

Levels of histone acetylation and phosphorylation have been contrasted in two developmental states of Drosophila melanogaster. The 0-2 h nuclei of the syncitial blastula are characterized by rapid mitoses and DNA replication, but there is very little transcription. In the 18 h embryo there is considerable transcription and the mitotic rate is much slower. It has been found that (1) histone H1 from 2h nuclei is not highly phosphorylated. This observation is not in accord with the view that H1 hyperphosphorylation is essential to mitosis, but is compatible with the hypothesis that H1 phosphorylation in Drosophila species is related to heterochromatization. (2) Histone H4 from 2 h embryos shows high levels of the diacetyl form (H4-Ac2), which is principally outside the nucleus. This accords with the hypothesis that H4-Ac2 is the form in which H4 is deposited on to newly replicated DNA and shows that H4 acetylation is linked not only to transcription. (3) Histone H3 acetylation is similar in 2h and in 18h embryos. As with H4, this acetylation probably correlates with chromatin assembly and is not transcription-related. (4) Histone H2B carries no modification in 2h or in 18h embryos, and H2A shows a single modification in 2h embryos and two in 18 h embryos. H2B modification is thus not essential either in mitosis or replication, whereas H2A modification is important in one or both processes. (5) The nucleosomal protein D2 is equally present in 2h and 18 h embryos.

Acetylation↗
PubMed2002

Connecting the DOTs: covalent histone modifications and the formation of silent chromatin.

Histone methylation has emerged as a significant regulator of chromatin structure and function. Two different classes of histone methyltransferase (HMT) have been described, which target either lysine or arginine residues in the histone N-terminal tails. A flurry of recent papers now describe a third class of HMT that affects chromatin silencing indirectly, not by methylation of histone tails, but instead by targeting a conserved lysine residue in the core domain of the nucleosome.

Animals↗
PubMed1981

Quantitative determination of histone modification. H2A acetylation and phosphorylation.

Each variant of histone 2A from mouse L1210 cells separates into at lest three bands on acid-urea gels, an unmodified band b0, and modified bands b1, b2, and, in the case of H2A.Z, b3. By analyzing tryptic peptides from these proteins on 50% acrylamide peptide gels, one can quantitate the fraction of H2A modified in various ways. With this methodology, the b1 form of H2A.1 was found to be a mixture of molecules, two-thirds of which were acetylated at lysine5 and one-third of which were phosphorylated at serine1. The b2 band of H2A.1 contained molecules with phosphorylated serine1, acetylated lysine5, and one or two other sites of modification not found in b1 H2A.1 b2 H2A.1 was not composed solely of molecules each with both a phosphorylated serine1 and an acetylated lysine5. The heteromorphous H2A variant H2A.X can be phosphorylated and acetylated. The phosphorylation site was the same as in H2A.1, but the acetylation site was slightly different. The heteromorphous variant H2A.Z was different from the other H2As in that it was not phosphorylated, and it did not contain the NH2-terminal peptide, which is the phosphorylation site in the .X, .1, and .2 variants. Its acetylation pattern was also different from that of H2A.1 in that two sites, neither of which was found in H2A.1, seem to be involved at the first level of modification.

Acetylation↗
PubMed2024

Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models.

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

Animals↗
PubMed2002

Histone modifications in transcriptional regulation.

Covalent modifications of the amino termini of the core histones in nucleosomes have important roles in gene regulation. Research in the past two years reveals these modifications to consist of phosphorylation, methylation and ubiquitination, in addition to the better-characterized acetylation. This multiplicity of modifications, and their occurrence in patterns and dependent sequences, argues persuasively for the existence of a histone code.

Acetylation↗
PubMed2001

Histone variants and histone modifications: a structural perspective.

In this review, we briefly analyze the current state of knowledge on histone variants and their posttranslational modifications. We place special emphasis on the description of the structural component(s) defining and determining their functional role. The information available indicates that this histone "variability" may operate at different levels: short-range "local" or long-range "global", with different functional implications. Recent work on this topic emphasizes an earlier notion that suggests that, in many instances, the functional response to histone variability is possibly the result of a synergistic structural effect.

Acetylation↗
PubMed1981

Histone modifications in the yeast S. Cerevisiae.

The content of the acetylated histone species associated with the highly transcriptionally active chromatin of yeast was examined. We found yeast chromatin to contain very high levels of the acetylated species for histones H3, H4 and possibly the H2B variants, H2B-1 and H2B-2. Sixty-three percent of the histone H4 species was represented by the di-, tri- and tetra-acetylated forms. These results make yeast chromatin among the most highly acetylated of any chromatins reported thus far. In addition, the results are consistent with the idea that hyperacetylation of histones allows chromatin to be transcribed at an increased rate.

Acetylation↗
PubMed2002

Dependence of histone modifications and gene expression on DNA hypermethylation in cancer.

We examined the relationship between aberrant DNA hypermethylation and key histone code components at a hypermethylated, silenced tumor suppressor gene promoter in human cancer. In lower eukaryotes, methylated H3-lysine 9 (methyl-H3-K9) determines DNA methylation and correlates with repressed gene transcription. Here we show that a zone of deacetylated histone H3 plus methyl-H3-K9 surrounds a hypermethylated, silenced hMLH1 promoter, which, when unmethylated and active, is embedded in methyl-H3-K4 and acetylated H3. Inhibiting DNA methyltransferases, but not histone deacetylases, leads first to promoter demethylation, second to gene reexpression, and finally to complete histone code reversal. Our findings suggest a new paradigm-DNA methylation may directly, or indirectly by inhibiting transcription, maintain key repressive elements of the histone code at a hypermethylated gene promoter in cancer.

Acetylation↗
PubMed1975

Histone modification in liver after administration of inducers of mixed function oxidase activity.

The phosphorylation and acetylation of rat liver histones in vivo were determined after administration of phenobarbital or 3-methylcholanthrene. No changes were observed in the phosphorylation profile of histones separated by gel electrophoresis after treatment with either of these two inducing agents. However, after 2h of treatment with either phenobarbital or 3-methylcholanthrene, a significant increase in acetylation of histones was noted, particularly in the F2a1 and (F3, F2b, F2a2) regions. It is suggested that this increase which precedes the enhancement in RNA synthesis may play a role in the alteration of transcription in liver.

Acetates↗
PubMed1983

Extent of histone modifications and H1(0) content during cell cycle progression in the presence of butyrate.

The effects of butyrate upon the extents of phosphorylation of histones H1 and H1(0) during cell-cycle progression have been investigated. Chinese hamster (line CHO) cells were synchronized in early S phase and released into medium containing 0 or 15 mM butyrate to resume cell-cycle traverse into G1 of the next cell cycle. Cells were also mechanically selected from monolayer cultures grown in the presence of colcemid and 0 or 15 mM butyrate to obtain greater than 98% pure populations of metaphase cells. Although cell cycle progression is altered by butyrate, electrophoretic patterns of histones H1, H1(0), H3, and H4 indicate that butyrate has little, if any, effect on the extents of H1 and H1(0) phosphorylation during the cell cycle or the mitotic-specific phosphorylation of histone H3. Butyrate does, however, inhibit removal of extraordinary levels of histone H4 acetylation (hyperacetylation) during metaphase, and it appears to cause an increase in the content of H1(0) in chromatin during the S or G2 phases of the cell cycle.

Acetylation↗
PubMed1987

Histone modifications accompanying the onset of developmental commitment.

In the sea urchin, Strongylocentrotus purpuratus, three cell types comprise the 16-cell stage embryo: micromeres, macromeres, and mesomeres. We have analyzed these three cell types for nuclear proteins that were synthesized during the earliest stages of embryonic development. The most striking differences in composition of newly synthesized proteins were found between the micromeres, which are the most committed cell type, and the macromeres and mesomeres. First, the micromeres lacked triply modified forms of histone H3; the levels of doubly modified forms of H3 were also greatly reduced. In contrast, micromeres were enriched in a band which migrated at the position of unmodified, unacetylated, histone H3 protein. Second, the overall distribution of H2A histone variants differed among the three cell types. Compared with macromeres and mesomeres, micromeres had a higher ratio of alpha-stage to cleavage-stage (CS) histone H2A; the micromere nuclei were depleted by 50 and 35%, respectively, in embryonically synthesized histone CS-H2A. Third, micromeres displayed different profiles of H1 histones. (a) They contained a cleavage-stage H1 histone which migrated faster than that of macromeres and mesomeres. This protein displays the electrophoretic behavior expected for a protein with reduced levels of posttranslational covalent modification. (b) Micromeres also had reduced levels of an H1 histone (designated H1 alpha a) band found in the alpha-H1 region of macromeres and mesomeres. These changes in chromatin modification correlate with the degree of commitment of cells in the developing embryo; they may reflect differing activities of the chromatin modifying enzymes in the various cell types at the 16-cell stage. Thus, the newly synthesized chromatin proteins of the individual blastomere types already differ in the developing sea urchin by the 16-cell stage. We suggest that variations in histone subtypes and in the levels of activity of chromatin modifying enzymes, e.g., acetylases and phosphorylases, could be involved in commitment and differentiation of different cell types.

Acetylation↗
PubMed1992

Reversible histone modifications and the chromosome cell cycle.

During the eukaryotic cell cycle, chromosomes undergo large structural transitions and spatial rearrangements that are associated with the major cell functions of genome replication, transcription and chromosome condensation to metaphase chromosomes. Eukaryotic cells have evolved cell cycle dependent processes that modulate histone:DNA interactions in chromosomes. These are; i) acetylations of lysines; ii) phosphorylations of serines and threonines and iii) ubiquitinations of lysines. All of these reversible modifications are contained in the well-defined very basic N- and C-terminal domains of histones. Acetylations and phosphorylations markedly affect the charge densities of these domains whereas ubiquitination adds a bulky globular protein, ubiquitin, to lysines in the C-terminal tails of H2A and H2B. Histone acetylations are strictly associated with genome replication and transcription; histone H1 and H3 phosphorylations correlate with the process of chromosome condensation. The subunits of histone H1 kinase have now been shown to be cyclins and the p34CDC2 kinase product of the cell cycle control gene CDC2. It is probable that all of the processes that control chromosome structure:function relationships are also involved in the control of the cell cycle.

Acetylation↗