NSD1-mediated HDAC1 recruitment reduces H3K27ac at active enhancers to safeguard associated gene expression
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ABSTRACT:
PROVIDER: PRJNA714969 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13983300_1.fastq.gz | Fastqsanger.gz | |||
| SRR13983300_2.fastq.gz | Fastqsanger.gz | |||
| SRR13983301_1.fastq.gz | Fastqsanger.gz | |||
| SRR13983301_2.fastq.gz | Fastqsanger.gz | |||
| SRR13983302_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetics, especially histone marks, functions beyond the DNA sequences to regulate gene expression. Depletion of NSD1, which catalyzes H3K36me2, led to both up- and down-regulation of gene expression, indicating NSD1 is associated with both active and repressed gene expression. It’s known that NSD1 regulates the deposition and expansion of H3K27me3, a repressive mark for gene expression, to keep active gene transcription. However, how NSD1 functions to repress gene expression is largely unknown. Here, we found that, when NSD1 was knocked out in mouse embryonic stem cells (mESCs), H3K27ac increased correlatively with the decrease of H3K36me2 at active enhancers, which is associated with mesoderm differentiation genes, leading to elevated gene expression. Mechanistically, NSD1 recruits HDAC1, the deacetylase of H3K27ac, to chromatin. Moreover, HDAC1 knockout (KO) recapitulates the increase of H3K27ac at active enhancers as the NSD1 depletion. Together, we propose that NSD1 deposits H3K36me2 and recruits HDAC1 at active enhancers to serve as a ‘safeguard’, preventing further activation of active enhancer-associated genes.
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Project description:Zygotic genome activation (ZGA) is an impressed biological event following fertilization during early embryo development. Precise reprogramming of epigenetic modifications (e.g. histone H3 lysine 27 acetylation, H3K27ac) have been found contribute to safeguard ZGA in zebrafish and Drosophila, but the dynamic of H3K27ac and the underlying regulation mechanism in mammal embryos are still enigmatic yet. As the main erasers for histone acetylation, histone deacetylase 1 and 2 (HDAC1 and HDAC2) are reported essential for mouse oogenesis and embryo lineage development, while it is unclear if they are functional for ZGA. Here, we observed significant global decrease of H3K27ac during ZGA in both mouse and bovine embryos, and accumulation of HDAC1/2 is responsible for the decline of H3K27ac. Repression of HDAC1/2 by dominant negative mutation led to arrested development at late 2-cell stage in mouse embryos, accompanied by downregulation of genes supposed to be expressed during ZGA. ChIP-seq revealed abnormal distribution of H3K27ac, and DUX participates in H3K27ac aberrant hyper-acetylation in embryos overexpressed mutant HDAC1/2. Moreover, suppression of HDAC1/2 also restrains H3K4me3 removal at gene body regions via impeding expression of KDM5s during mouse ZGA, and compensatory exogenous Kdm5b mRNA can fix the exceeding H3K4me3 and failed ZGA. Intriguingly, function of HDAC1/2 seems to be conservative between mouse and bovine embryos. Together, this study reveals that HDAC1/2 is indispensable for mouse and bovine ZGA via regulating distribution of H3K27ac and H3K4me3.
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Project description:Zygotic genome activation (ZGA) is an impressed biological event following fertilization during early embryo development. Precise reprogramming of epigenetic modifications (e.g. histone H3 lysine 27 acetylation, H3K27ac) have been found contribute to safeguard ZGA in zebrafish and Drosophila, but the dynamic of H3K27ac and the underlying regulation mechanism in mammal embryos are still enigmatic yet. As the main erasers for histone acetylation, histone deacetylase 1 and 2 (HDAC1 and HDAC2) are reported essential for mouse oogenesis and embryo lineage development, while it is unclear if they are functional for ZGA. Here, we observed significant global decrease of H3K27ac during ZGA in both mouse and bovine embryos, and accumulation of HDAC1/2 is responsible for the decline of H3K27ac. Repression of HDAC1/2 by dominant negative mutation led to arrested development at late 2-cell stage in mouse embryos, accompanied by downregulation of genes supposed to be expressed during ZGA. ChIP-seq revealed abnormal distribution of H3K27ac, and DUX participates in H3K27ac aberrant hyper-acetylation in embryos overexpressed mutant HDAC1/2. Moreover, suppression of HDAC1/2 also restrains H3K4me3 removal at gene body regions via impeding expression of KDM5s during mouse ZGA, and compensatory exogenous Kdm5b mRNA can fix the exceeding H3K4me3 and failed ZGA. Intriguingly, function of HDAC1/2 seems to be conservative between mouse and bovine embryos. Together, this study reveals that HDAC1/2 is indispensable for mouse and bovine ZGA via regulating distribution of H3K27ac and H3K4me3.
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