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Retrotransposon-driven co-transcriptional chromatin remodelling rewires Ash2l isoform usage to prime developmental promoters [ChIP-seq]

ABSTRACT: Transcription start site (TSS) selection diversifies the transcriptome and proteome, yet the mechanisms and functional consequences of alternative TSSs in development remain poorly understood. Here, we show that the chromatin regulator ASH2L undergoes developmentally regulated alternative TSS switching in differentiating mouse cells, generating distinct mRNA and protein isoforms: a full-length ASH2L and a truncated form lacking an intrinsically disordered region (IDR). In pluripotent stem cells, transcription from the upstream TSS is driven by a mouse-specific retrotransposon element that suppresses transcription from the downstream TSS through a transcription interference mechanism involving SETD2-directed histone H3 lysine 36 methylation. The resulting upstream-driven, stem cell–specific truncated ASH2L isoform primes developmental-gene promoters for histone H3 lysine 4 methylation, establishing a chromatin state required for embryogenesis and motor neuron differentiation. We propose that co-option of a mouse-specific retrotransposon drives a switch in Ash2l TSS and protein isoforms to control developmental timing and cell fate decisions.

ORGANISM(S): Mus musculus

PROVIDER: GSE320327 | GEO | 2026/03/03

REPOSITORIES: GEO

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Retrotransposon-driven co-transcriptional chromatin remodelling rewires Ash2l isoform usage to prime developmental promoters [Timecourse]

Project description:Transcription start site (TSS) selection diversifies the transcriptome and proteome, yet the mechanisms and functional consequences of alternative TSSs in development remain poorly understood. Here, we show that the chromatin regulator ASH2L undergoes developmentally regulated alternative TSS switching in differentiating mouse cells, generating distinct mRNA and protein isoforms: a full-length ASH2L and a truncated form lacking an intrinsically disordered region (IDR). In pluripotent stem cells, transcription from the upstream TSS is driven by a mouse-specific retrotransposon element that suppresses transcription from the downstream TSS through a transcription interference mechanism involving SETD2-directed histone H3 lysine 36 methylation. The resulting upstream-driven, stem cell–specific truncated ASH2L isoform primes developmental-gene promoters for histone H3 lysine 4 methylation, establishing a chromatin state required for embryogenesis and motor neuron differentiation. We propose that co-option of a mouse-specific retrotransposon drives a switch in Ash2l TSS and protein isoforms to control developmental timing and cell fate decisions.

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Induction of senescence upon loss of the Ash2l subunit of histone H3K4 methyltransferase complexes (ChIP-Seq)

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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Project description:The Ash2l protein is a member of KMT2 enzyme complexes, which catalyse the (tri-)methylation of lysine 4 of Histone H3. H3K4me3 is considered a marker of actively transcribed genes. We determined changes in gene expression as a consequence of a conditional loss of Ash2l in the bone marrow. The expression data from the bone marrows of mice with floxed Ash2l exon 4 alleles without (control) or with an Mx1-Cre transgene (KO) and treated with synthetic dsRNA to induce recombination and the loss of Ash2l protein expression were compared.

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Project description:The trithorax protein ASH2L is essential for organismal and tissue development and for cell proliferation. ASH2L is a subunit of KMT2/COMPASS methyltransferase complexes that catalyze the methylation of histone H3 lysine 4 (H3K4). Tri- and mono-methylation of H3K4 (Ash2l and H3K4me1) are associated with active promoters and enhancers, respectively. The molecular relevance of these modifications is not fully understood. We have used mouse embryo cells with a PROTAC-sensitive, degradable ASH2L to assess the functional consequences of KMT2 complex inactivation. The rapid loss of ASH2L resulted in a sequential alterations of histone marks at promoters, first a decrease of Ash2l, then an increase of H3K4me1, and a decrease of H3K27ac during the first 16 hrs, while an increase in H3K27me3 was very slow. These consequences were most prominent at CpG island promoters within a window of ±1 kb of the transcription start sites. Despite the the rapid loss of ASH2L, the effect on transcription in the first 8 hrs was minimal. This was accompanied with an alterations in gene expression and associated proliferation stop and cell cycle arrest. These findings suggest an order series of events upon loss of ASH2L that requires considerable amount of time to unfold.

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Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes promotes chromatin compaction at promoters [ChIP-seq H3K4me1,me3]

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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