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Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells [RNA-Seq]

ABSTRACT: Polycomb repressive complex 2 (PRC2) regulates gene expression during lineage specification through trimethylation of lysine 27 on histone H3 (H3K27me3). In Drosophila, polycomb binding sites are dynamic chromatin regions coupled to incorporation of the histone variant H3.3. Here we show in mouse embryonic stem cells (ESCs) that H3.3 is required for proper establishment of H3K27me3 at the promoters of developmentally regulated genes. These promoters show reduced dynamics as determined by deposition of de novo synthesized histones, associated with reduced PRC2 occupancy. H3.3-depleted ESCs show upregulation of extraembryonic trophectoderm, as well as misregulation of other developmental genes upon differentiation. Our data demonstrate the importance of H3.3 incorporation in ESCs and suggest that changes in chromatin dynamics in its absence lead to misregulation of gene expression during differentiation. Moreover, our findings lend support to the emerging notion that H3.3 has multiple functions in distinct genomic locations that are not always correlated with an “active” chromatin state.

ORGANISM(S): Mus musculus

PROVIDER: GSE42154 | GEO | 2013/09/30

SECONDARY ACCESSION(S): PRJNA179217

REPOSITORIES: GEO

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Project description:Histone variants and their chaperones are key regulators of eukaryotic transcription, and are critical for normal development. The histone variant H3.3 has been shown to play important roles in pluripotency and differentiation, and although its genome-wide patterns have been investigated, little is known about the role of its dynamic turnover in transcriptional regulation. To elucidate the role of H3.3 dynamics in embryonic stem cell (ESC) biology, we generated mouse ESC lines carrying a single copy of a doxycycline (Dox)-inducible HA-tagged version of H3.3, and monitored the rate of incorporation of the HA-tagged variant by ChIP-seq at varying time points following Dox induction. Active H3K4me3-enriched genes display high turnover dynamics in transcription start sites (TSS); H3K27me3-enriched genes have a lower turnover dynamics in the TSS, but higher turnover rates in gene bodies; developmental bivalent genes marked by both H3K4me3 and H3K27me3 show a mixed behavior with high TSS dynamics and high gene body dynamics, especially in genes bound by both PRC1 and PRC2. In contrast, genes proximal to super-enhancers show the most reduced gene-body turnover dynamics, while genes proximal to other enhancers show no unique pattern. In RA-treated cells, while the overall profile in expressed genes remains largely unaltered over the TSS and gene body, a significant and dramatic decrease in turnover occurs at the -1 nucleosome position immediately before the TSS, revealing a hyperdynamic nucleosome in promoters of genes expressed in ESCs. We suggest that histone turnover dynamics provides an additional mechanism involved in expression regulation, that gene-body turnover dynamics is distinct from that of promoter regions, and that a hyperdynamic -1 nucleosome marks promoters in ESCs. Our data provide evidence for regional regulation of H3.3 turnover in ESC promoters, and calls for testing, in high resolution, the dynamic behavior of additional histone variants and other structural chromatin proteins.

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Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells [RNA-Seq]

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