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

ABSTRACT: 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.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE122335 | GEO | 2019/02/06

REPOSITORIES: GEO

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

Project description:An unstructured MET-2/SETDB1 cofactor ensures H3K9me2, focus formation and perinuclear anchoring

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

Project description:An unstructured MET-2/SETDB1 cofactor ensures H3K9me2, focus formation and perinuclear anchoring [ChIP-seq]

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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.

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Two parallel pathways recruit the H3K9me3 HMT in somatic cells, requiring the Argonaut NRDE-3, or the MBT-domain protein, LIN-61 (smallRNA-seq)

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