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Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes promotes chromatin compaction at promoters.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE205233 | GEO | 2022/12/13

REPOSITORIES: GEO

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Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes promotes chromatin compaction at promoters [ATAC-seq]

Project description:Cell fate decisions are closely associated with changes in gene expression programs. A large number of post-translational modifications of core histones contribute to controlling the expression of genes. A modification that is closely correlated with open chromatin and gene transcription is methylation of lysine 4 of histone H3 (H3K4). It is catalyzed by methyltransferases of the KMT2 family, which require interaction with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, for catalytic activity. Ash2l is required for organismal development and for tissue homeostasis in the mouse. In mouse embryo fibroblasts (MEFs), the loss of Ash2l results in downregulated gene expression, which provokes a senescence phenotype. We now find that both H3K4 mono- and tri-methylation (H3K4me1 and me3, respectively) are deregulated. H3K4me3 is lost while H3K4me1 is increased at promoters upon knockout of Ash2l. In particular, loss of H3K4me3 at promoters correlates with downregulation of gene expression, which is particularly obvious at CpG island promoters. Ash2l loss results in an increase of histone H3 loading at promoters, paralleled by enhanced chromatin compaction. This is accompanied by an increase of repressing and a decrease of activating histone marks. One of the sequence-specific transcription factors with altered binding upon depletion of Ash2l is CTCF. It is lost from some promoter-associated sites, but gained binding in other regions of the genome. This suggests that in addition to the well-known effects on H3K4 methylation upon depleting KMT2 complex components, Ash2l loss affects chromatin compaction. Whether the decrease of H3K4me3 promotes chromatin compaction at promoters or whether these are independent consequences of Ash2l loss remains to be determined. We suggest that both contribute mechanistically to gene repression and thus to the observed cellular effects.

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Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes promotes chromatin compaction at promoters [ChIP-seq CTCF]

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Project description:Post-translational modifications of core histones participate in controlling the expression of genes. Methylation of lysine 4 of histone H3 (H3K4) is associated with open chromatin and gene transcription. This histone mark is catalyzed by type 2 lysine methyltransferase (KMT2) complexes. In mammals, these consist of one of 6 different KMT2 enzymes, each associated with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, which are necessary for catalytic activity. The knockout of Ash2l is embryonically lethal in mice as well as in adult animals when hepatocytes or hematopoietic cells are targeted. To expand on the mechanistic understanding of Ash2l, we have used mouse embryo fibroblasts (MEFs). The knockout of Ash2l resulted in the downregulation of H3K4me3 at a large number of promoters, preferentially those associated with CpG islands, accompanied with broad repression of gene expression. The consequence in MEFs was induction of senescence concomitant with a set of down-regulated signature genes. Thus, although the loss of Ash2l in MEFs has broad and complex consequences on the transcriptional program, the biological consequences were distinct, culminating in senescence.

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Structure and Conformational Dynamics of a COMPASS Histone H3K4 Methyltransferase Complex.

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