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A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis [RNA-seq]

ABSTRACT: Packaging genomic regions into silenced heterochromatin is critical to maintain organismal viability and tissue identity. Methylation of histone H3 on lysine 9 (H3K9me) marks heterochromatin. Here we show that in addition to catalyzing H3K9me, the C. elegans histone methyltransferase MET-2 (SETDB1-like) has a second non-catalytic function that can itself contribute to gene repression. We find that subnuclear concentrates, or foci, of MET-2 correlate with efficient HMT activity, yet foci composed of catalytic-deficient MET-2 are also able to mediate transcriptional silencing. Genetic ablation of met-2 or physiological disruption of MET-2 foci by heat stress results in loss of silencing coincident with an increase in histone acetylation. Restoration of catalytically deficient MET-2 foci mitigates H3K9 and H3K27 hyperacetylation, gene derepression, and infertility, demonstrating a structural role for foci of a conserved heterochromatic histone methyltransferase in gene silencing independent of its enzymatic activity.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE168924 | GEO | 2021/08/01

REPOSITORIES: GEO

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A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis [ChIP-seq]

Project description:Packaging genomic regions into silenced heterochromatin is critical to maintain organismal viability and tissue identity. Methylation of histone H3 on lysine 9 (H3K9me) marks heterochromatin. Here we show that in addition to catalyzing H3K9me, the C. elegans histone methyltransferase MET-2 (SETDB1-like) has a second non-catalytic function that can itself contribute to gene repression. We find that subnuclear concentrates, or foci, of MET-2 correlate with efficient HMT activity, yet foci composed of catalytic-deficient MET-2 are also able to mediate transcriptional silencing. Genetic ablation of met-2 or physiological disruption of MET-2 foci by heat stress results in loss of silencing coincident with an increase in histone acetylation. Restoration of catalytically deficient MET-2 foci mitigates H3K9 and H3K27 hyperacetylation, gene derepression, and infertility, demonstrating a structural role for foci of a conserved heterochromatic histone methyltransferase in gene silencing independent of its enzymatic activity.

2021-08-01 | GSE168923 | GEO

A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis

Project description:A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis

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A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis [RNA-seq]

Project description:A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis [RNA-seq]

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A structural role for histone methyltransferase MET-2 represses transcription independent of H3K9me catalysis [ChIP-seq]

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Automethylation-induced conformational switch in Clr4 (Suv39h) maintains epigenetic stability

Project description:Histone H3 lysine 9 methylation (H3K9me) mediates heterochromatic gene silencing and is important for genome stability and the regulation of gene expression. The establishment and epigenetic maintenance of heterochromatin involve the recruitment of H3K9 methyltransferases to specific sites on DNA, followed by the recognition of pre-existing H3K9me by the methyltransferase and methylation of proximal histone H3. This positive feedback loop must be tightly regulated to prevent deleterious epigenetic gene silencing. Extrinsic anti-silencing mechanisms involving histone demethylation or boundary elements help limit the spread of inappropriate H3K9me. However, how H3K9 methyltransferase activity is locally restricted or prevented from initiating random H3K9me—which would lead to aberrant gene silencing and epigenetic instability—is not fully understood. Here we reveal an autoinhibited conformation in the conserved H3K9 methyltransferase Clr4 (Suv39h) of the fission yeast Schizosaccharomyces pombe that has a critical role in preventing aberrant heterochromatin formation. Biochemical and X-ray crystallographic data show that an internal loop in Clr4 inhibits the catalytic activity of this enzyme by blocking the histone H3K9 substrate-binding pocket, and that automethylation of specific lysines in this loop promotes a conformational switch that enhances the H3K9me activity of Clr4. Mutations that are predicted to disrupt this regulation lead to aberrant H3K9me, loss of heterochromatin domains, and growth inhibition, demonstrating the importance of the intrinsic inhibition and auto-activation of Clr4 in regulating the deposition of H3K9me and in preventing epigenetic instability. Together, conservation of the Clr4 autoregulatory loop in other H3K9 methyltransferases and the automethylation of a corresponding lysine in the human SUV39H2 homologue suggest that the mechanism described here is broadly conserved.

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An unstructured MET-2/SETDB1 cofactor ensures H3K9me2, focus formation and perinuclear anchoring [RNA-seq]

Project description:The segregation of the genome into accessible euchromatin and histone H3 lysine 9 methylated (H3K9me) heterochromatin is essential for the repression of repetitive elements and tissue-specific genes. In C. elegans, the SETDB1 homolog MET-2 catalyzes H3K9me1 and me2. In worms as in vertebrates, the regulation of this crucial enzyme remains enigmatic. Contrary to the localization of overexpressed MET-2, we find endogenous MET-2 to be nuclear throughout development, enriched in perinuclear foci in a cell cycle-dependent manner. We show by mass spectrometry that MET-2 associates with a highly unstructured protein, LIN-65, and a conserved GTPase effector ARLE-14. All three colocalize at heterochromatic foci. Ablation of lin-65, but not arle-14, mislocalizes and destabilizes MET-2, resulting in decreased H3K9me2, derepression of MET-2 targets, and loss of fertility. Importantly, mutation of met-2 or lin-65 is sufficient to disrupt the perinuclear clustering of heterochromatin genome-wide. Thus, LIN-65 is an essential cofactor of MET-2 required for H3K9me2 deposition, heterochromatin clustering, perinuclear anchoring, and transcriptional repression.

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A Composite DNA Element that Functions as a Maintainer Required for Epigenetic Inheritance of Heterochromatin

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

PHF2-mediated H3K9me balance orchestrates heterochromatin stability and progenitor proliferation in early neurogenesisPHF2-mediated H3K9me balance orchestrates heterochromatin stability and progenitor proliferation in early neurogenesis

Project description:Heterochromatin stability is crucial for progenitor proliferation during early neurogenesis. It relays on the maintenance of local hubs of H3K9me. However, the current understanding of the processes involved in the formation of efficient localized levels of H3K9me remains limited. To address this intriguing question, we used a neural stem cell (NSC) to analyze the function of the H3K9me2 demethylase PHF2, which is crucial for progenitor proliferation. Through mass spectroscopy and genome-wide assays, we uncovered that PHF2 interacts with heterochromatin components and it is enriched at pericentromeric heterochromatin (PcH) boundaries. This binding is essential for maintaining silenced the satellite repeats thereby preventing DNA damage and genome instability. Depletion of PHF2 led to increased transcription of heterochromatic repeats, accompanied by a decrease in H3K9me3 levels and alterations in PcH organization. Further analysis revealed that PHF2's PHD and catalytic domains are crucial for maintaining PcH stability and preventing unscheduled repeat transcription, thereby safeguarding genome integrity. These results highlight the multifaceted nature of PHF2's functions in maintaining heterochromatin stability and regulating gene expression during neural development. Altogether, our study unravels the intricate relationship between heterochromatin stability and progenitor proliferation during mammalian neurogenesis, shedding light on its potential as a therapeutic target for neurodevelopmental disorders

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H3K9me blocks transcription factor activity in differentiated cells to ensure tissue integrity [RNA-seq]

Project description:Development in multicellular organisms is governed by a carefully orchestrated program of gene expression controlled by both genetic and epigenetic factors1,2. Histone H3 lysine 9 methylation (H3K9me) is the defining modification of heterochromatin, which is thought to have two main functions. It silences satellite repeats and transposable elements to ensure genome stability3, and stabilizes differentiated states by repressing tissue-specific genes4,5. Not surprisingly, the loss of appropriately targeted heterochromatin is associated with cancer, loss of tissue integrity, and aging5-8. How H3K9me restricts transcription is unknown. Here we show that in C. elegans H3K9me2 is required to silence different sets of genes in embryos and differentiated post-mitotic cells. During nematode development H3K9me is lost from genes that define cell-type identity and is gained at genes expressed at prior stages or in alternative tissues. We found that a continuous deposition of H3K9me2 is necessary to maintain silencing in terminally differentiated cells. Its loss leads to DNA decompaction, but this is not sufficient to derepress H3K9me-marked genes. Instead, gene derepression in differentiated tissues requires distinct sets of transcription factors (TF) that aberrantly activate enhancers or promoters. Tissue-specific H3K9me distribution thus contributes critically to cell-type specific TF binding providing a rationale for how a limited set of TFs can control complex organismal development9,10.

2021-08-01 | GSE167167 | GEO

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