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Symmetric inheritance of parental histones governs epigenome maintenance and stem cell identity [ChIP-seq]

ABSTRACT: Symmetric inheritance of parental histones governs epigenome maintenance and stem cell identity [ChIP-seq]

PROVIDER: PRJNA646067 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12214700.fastq.gz	Fastqsanger.gz
	SRR12214701.fastq.gz	Fastqsanger.gz
	SRR12214702.fastq.gz	Fastqsanger.gz
	SRR12214643.fastq.gz	Fastqsanger.gz
	SRR12214645.fastq.gz	Fastqsanger.gz

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Symmetric inheritance of parental histones governs epigenome maintenance and stem cell identity

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Symmetric inheritance of parental histones governs epigenome maintenance and stem cell identity

Project description:Modified parental histones are segregated symmetrically to daughter DNA strands during replication and inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here, we show that transmission of histone-based information during replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused de-repression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Further, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian differentiation.

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MCM2 promotes symmetric inheritance of modified histones during DNA replication

Project description:During genome replication, parental histones are recycled to newly replicated DNA with their post-translational modifications (PTMs). It remains unknown whether sister chromatids inherit modified histones evenly. Here, we measured histone PTM partition to sister chromatids in embryonic stem cells. We found that parental histones H3-H4 segregate to both daughter DNA strands with a weak leading strand bias, skewing partition at topologically associating domain (TAD) borders and enhancers proximal to replication initiation zones. Segregation of parental histones to the leading strand increased markedly in cells with histone-binding mutations in MCM2, part of the replicative helicase, exacerbating histone PTM sister chromatid asymmetry. This work reveals how histones are inherited to sister chromatids and identifies a mechanism for how symmetric cell division is ensured by the replication machinery.

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