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Genome wide nucleosome specifity and function of chromatin remodellers in embryonic stem cells [Chd6]

ABSTRACT: How various ATP-dependent chromatin remodellers bind to nucleosomes to regulate transcription is not well defined in mammalian cells. Here, we present genome-wide remodeller-interacting nucleosome profiles for Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind to nucleosomes at specific positions, either at one or both nucleosomes that flank each side of nucleosome-free promoter regions (NFRs), at enhancer elements, or within gene bodies. At promoters, bidirectional transcription commonly initiates on either side of remodeller-bound nucleosomes. Transcriptome analysis upon remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. At active genes, certain remodellers are positive regulators of transcription, whereas others act as repressors. At bivalent genes, which are bound by repressive Polycomb complexes, the same remodellers act in the opposite way. Together, these findings reveal how remodellers integrate promoter nucleosomal architecture to regulate ES cell transcription programs.

ORGANISM(S): Mus musculus

PROVIDER: GSE64782 | GEO | 2016/01/26

SECONDARY ACCESSION(S): PRJNA272935

REPOSITORIES: GEO

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Project description:SWI/SNF-family chromatin remodelling complexes conduct nucleosome sliding and ejection to provide DNA-binding proteins access to their sites in chromatin. RSC is an essential and abundant SWI/SNF-family chromatin remodeller from S. cerevisiae that both slides and ejects nucleosomes. However, how ejection versus sliding is chosen, regulated and implemented by any remodeller remains largely unknown. The RSC catalytic subunit Sth1 conducts ATP-dependent DNA translocation, pumping DNA around the nucleosome, providing a property that might underlie both sliding and ejection. Sth1 shares with other SWI/SNF-family ATPases direct binding to two nuclear actin-related proteins (ARPs), but how ARPs impact DNA translocation, sliding and ejection is unknown. Here, we reveal that nucleosome ejection by RSC requires ARPs, and that ARPs improve ‘coupling’ – the efficiency of DNA translocation by Sth1 relative to ATP hydrolysis – thus, enhancing DNA translocation. We further characterize two domains within Sth1 (termed PTH and P1), showing they separately regulate ATP hydrolysis or ‘coupling’, respectively. Interestingly, gain-of-function PTH or P1 mutations suppress arpΔ lethality, and improve ATPase or coupling activities, enabling Sth1 to efficiently slide and eject nucleosomes without ARPs. Moreover, PTH mutations greatly improved DNA translocation velocity. Overall, our results provide a logic for regulating nucleosome sliding versus ejection: both modes involve DNA translocation, but ejection requires a higher magnitude. Here, low-to-moderate ATPase and coupling activity integrate to confer low-to-moderate sliding, whereas high ATPase and/or coupling combine to provide efficient and rapid DNA translocation, consistent with the simultaneous rupture of multiple histone-DNA contacts, causing histone loss/ejection. Our discovery of an ARP module and regulatory domains that regulate sliding and ejection suggests a mechanistic platform through which activators and histone epitopes may guide the remodelling outcome of SWI/SNF-family chromatin remodellers.

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Genome wide nucleosome specifity and function of chromatin remodellers in embryonic stem cells [Chd6]

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