A critical density of histone H3 lysine 9 tri-methylation is required for propagation of heterochromatin and epigenetic inheritance
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PROVIDER: PRJNA682632 | ENA |
REPOSITORIES: ENA
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Project description:A critical density of histone H3 lysine 9 tri-methylation is required for propagation of heterochromatin and epigenetic inheritance
| PRJNA682632 | ENA
Project description:Occupancy profiling of myc-tagged Raf1 protein in fission yeast. Occupancy profiling of lysine 9 dimethylated and trimethylated histone H3 in fission yeast.
2021-06-09 | GSE162701 | GEO
Project description:Heterochromatin assembly requires methylation of histone H3 lysine 9 (H3K9me) and serves as a paradigm for understanding the importance of histone modifications in epigenetic genome control. Heterochromatin is nucleated at specific genomic sites and spreads across extended chromosomal domains to promote gene silencing. Moreover, heterochromatic structures can be epigenetically inherited in a self-templating manner, which is critical for stable gene repression. The spreading and inheritance of heterochromatin are believed to be dependent on preexisting H3K9 tri-methylation (H3K9me3), which is recognized by the histone methyltransferase Clr4/Suv39h via its chromodomain, to promote further deposition of H3K9me. However, the process involving the coupling of the "read" and "write" capabilities of histone methyltransferases is poorly understood. From an unbiased genetic screen, we characterize a dominant-negative mutation in histone H3 (H3G13D) that impairs the propagation of endogenous and ectopic heterochromatin domains in the fission yeast genome. H3G13D blocks methylation of H3K9 by the Clr4/Suv39h methyltransferase and acts in a dosage-dependent manner to interfere with the spreading and maintenance of heterochromatin. Our analyses show that the incorporation of unmethylatable histone H3G13D into chromatin decreases H3K9me3 density and thereby compromises the read-write capability of Clr4/Suv39h. Consistently, enhancing the affinity of Clr4/Suv39h for methylated H3K9 is sufficient to overcome the defects in heterochromatin assembly caused by H3G13D Our work directly implicates methylated histones in the transmission of epigenetic memory and shows that a critical density threshold of H3K9me3 is required to promote epigenetic inheritance of heterochromatin through the read-write mechanism.
| S-EPMC8179192 | biostudies-literature
Project description:Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis. Here, we aimed to identify the chromatin signature(s) associated with transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that occurred independently from non-bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.
2020-10-15 | GSE145679 | GEO
Project description:Functional data indicate that specific histone modification enzymes can be key to longevity in Caenorhabditis elegans, but epigenetic mechanisms of lifespan regulation are not well understood. In this study, we profiled the genome-wide pattern of tri-methylation of lysine 36 on histone 3 (H3K36me3) in the somatic cells of young and old C. elegans. We revealed a new role of H3K36me3 in maintaining gene expression stability through aging with important consequence on longevity. We found that genes with dramatic expression change during aging are marked with low or even undetectable levels of H3K36me3 in their gene-bodies, irrespective of their corresponding mRNA abundance. Importantly, inactivation of the methyltransferase met-1 resulted in a decrease in global H3K36me3 marks, an increase in mRNA expression change with age, and a shortened lifespan, suggesting a causative role of the H3K36me3 marking in modulating age-dependent gene expression stability and longevity.
2015-04-01 | GSE62720 | GEO
Project description:Functional data indicate that specific histone modification enzymes can be key to longevity in Caenorhabditis elegans, but epigenetic mechanisms of lifespan regulation are not well understood. In this study, we profiled the genome-wide pattern of tri-methylation of lysine 36 on histone 3 (H3K36me3) in the somatic cells of young and old C. elegans. We revealed a new role of H3K36me3 in maintaining gene expression stability through aging with important consequence on longevity. We found that genes with dramatic expression change during aging are marked with low or even undetectable levels of H3K36me3 in their gene-bodies, irrespective of their corresponding mRNA abundance. Importantly, inactivation of the methyltransferase met-1 resulted in a decrease in global H3K36me3 marks, an increase in mRNA expression change with age, and a shortened lifespan, suggesting a causative role of the H3K36me3 marking in modulating age-dependent gene expression stability and longevity. We performed genome-wide mapping of histone H3 and H3K36me3 in young (D2A) and old (D12A) C.elegans somatic cells by ChIP-seq in glp-1(e2141). mRNA-seq was performed in young (D2A) and old (D12A) glp-1(e2141) somatic cells to identify mRNA expression change during aging from D2A to D12A.
2015-04-01 | E-GEOD-62720 | biostudies-arrayexpress
Project description:Post-translational modifications of histones play important roles in modulating chromatin structure and regulating gene expression. We have previously shown that over two thirds of Arabidopsis genes contain histone H3 methylation at lysine-4 (H3K4me), and that tri-methylation of H3K4 (H3K4me3) is preferentially located at actively transcribed genes. In addition, several Arabidopsis mutants with locus-specific loss of H3K4me have been found to display various developmental abnormalities. These findings suggest that H3K4me3 may play important roles in maintaining the normal expression of a large number of genes. However, the major enzyme(s) responsible for H3K4me3 has yet to be identified in plants, making it difficult to address questions regarding the mechanisms and functions of H3K4me3. Here we describe the characterization of SET DOMAIN GROUP 2 (SDG2), a large Arabidopsis protein containing a histone lysine methyltransferase domain. We found that SDG2 homologues are highly conserved in plants, and that the Arabidopsis SDG2 gene is broadly expressed during development. In addition, the loss of SDG2 leads to severe and pleiotropic phenotypes as well as the mis-regulation of a large number of genes. Consistent with our finding that SDG2 is a robust and specific H3K4 methyltransferase in vitro, the loss of SDG2 leads to a drastic decrease in H3K4me3 in vivo. Taken together, these results suggest that SDG2 is the major enzyme responsible for H3K4me3 in Arabidopsis, and that SDG2-dependent H3K4m3 is critical for regulating gene expression and plant development.
2010-10-11 | GSE23208 | GEO
Project description:In higher eukaryotes, a single DOT1 histone H3 lysine 79 (H3K79) methyltransferase processively produces H3K79me2/me3 from me0 through histone H2B mono-ubiquitin interaction. The early-branched kinetoplastid Trypanosoma brucei harbors the essential H3K76 di-methyltransferase DOT1A and the non-essential DOT1B H3K76 tri-methyltransferase, which methylate their substrates without H2B mono-ubiquitination. It is not known how these enzymes efficiently maintain H3K76me3 without ubiquitin interaction in vivo. Here we discovered distinct methylation kinetics of DOT1A and DOT1B in vitro and identified kinetoplastid-specific key residues by structural analysis of DOT1A. DOT1A contains a unique N-terminal ?-hairpin domain and a conserved C-terminal methyltransferase core domain that exhibits significant deviations in the methyltransferase motifs IV, VI, and X. The motif X sequence VYGE is substituted to CAKS in a non-conserved, flexible active-site loop, implying a distinct mechanism for substrate H3K76 recognition. Substitution of a basic to an acidic residue within the canonical motif VI (Gx6K) at the putative DOT1A-nucleosome interface is essential for DOT1A-nucleosome interaction, which would stabilize the enzyme-substrate complex without ubiquitin interactions. Mass spectrometry-based kinetic data demonstrate that DOT1A favors H3K76me0, while DOT1B favors the DOT1A products H3K76me1 and me2. These substrate preferences are determined by Ser and Ala residues within motif IV of DOT1A and DOT1B, respectively. We show in vitro that the distinct substrate preferences enable DOT1A and DOT1B to catalyze H3K76 tri-methylation eight times faster than DOT1B alone, suggesting that efficient ubiquitin-independent H3K76 tri-methylation can be achieved non-processively through the cooperative action of two DOT1 enzymes in vivo.
2022-11-09 | MSV000090680 | MassIVE
Project description:Epigenetic inheritance of heterochromatin requires DNA sequence-independent propagation mechanisms, coupling to RNAi, or input from DNA sequence, but how DNA contributes to inheritance is not understood. Here, we identify a DNA element (termed “maintainer”) that is sufficient for epigenetic inheritance of preexisting histone H3 lysine 9 methylation (H3K9me) and heterochromatin in Schizosaccharomyces pombe, but cannot establish de novo gene silencing in wild-type cells. This maintainer is a composite DNA element with binding sites for the Atf1/Pcr1 and Deb1 transcription factors and the Origin Recognition Complex (ORC), located within a 130-base pair region, and can be converted to a silencer in cells with lower rates of H3K9me turnover, suggesting that it participates in recruiting the H3K9 methyltransferase Clr4/Suv39h. These results suggest that, in the absence of RNAi, histone H3K9me is only heritable when it can collaborate with maintainer-associated DNA-binding proteins that help recruit the enzyme responsible for its epigenetic deposition.
2022-10-14 | PXD027214 | Pride