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The histone variant H2A.Z is an important regulator of enhancer activity.

ABSTRACT: Gene regulatory programs in different cell types are largely defined through cell-specific enhancers activity. The histone variant H2A.Z has been shown to play important roles in transcription mainly by controlling proximal promoters, but its effect on enhancer functions remains unclear. Here, we demonstrate by genome-wide approaches that H2A.Z is present at a subset of active enhancers bound by the estrogen receptor alpha (ERα). We also determine that H2A.Z does not influence the local nucleosome positioning around ERα-enhancers using ChIP-sequencing at nucleosomal resolution and unsupervised pattern discovery. We further highlight that H2A.Z-enriched enhancers are associated with chromatin accessibility, H3K122ac enrichment and hypomethylated DNA. Moreover, upon estrogen stimulation, the enhancers occupied by H2A.Z produce enhancer RNAs (eRNAs), and recruit RNA polymerase II as well as RAD21, a member of the cohesin complex involved in chromatin interactions between enhancers and promoters. Importantly, their recruitment and eRNAs production are abolished by H2A.Z depletion, thereby revealing a novel functional link between H2A.Z occupancy and enhancer activity. Taken together, our findings suggest that H2A.Z acts as an important player for enhancer functions by establishing and maintaining a chromatin environment required for RNA polymerase II recruitment, eRNAs transcription and enhancer-promoters interactions, all essential attributes of enhancer activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57436 | GEO | 2015/08/31

SECONDARY ACCESSION(S): PRJNA246455

REPOSITORIES: GEO

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Project description:Estrogen receptors alpha (ERα) converges estrogen signaling by orchestrating estrogen (E2)-dependent transcription regulation. Upon binding to the chromatin, ERα serves as a nucleation site for de novo formation of transcription enhancer complexes. Steroid receptor coactivators family proteins (SRCs, a.k.a p160) and Mediator complex are the two coregulators for ERα that directly interact with the receptors and control enhancer activity by regulating recruitment of other coregulators and transcription machinery. Lysine acetyltransferase p300/CBP is also a critical coregulator for ERα that is recruited through SRCs in stable ERα enhancer complex. ERα enhancers exhibit common enhancer features including enrichment of enhancer-specific histone modification (e.g. H3K4me1 and H3K27ac), coregulator recruitment, and active transcription. Despite of recognition of those enhancer characteristics, the order of assembly and functions and the functional relationships among enhancer features during active enhancer complex formation is not well understood. Using the time course genomics and molecular biology assays, we dissect the order of assembly and functions of ERα enhancer complex formation. We describe the mechanism of SRC-independent p300 recruitment mediated by Mediator, leading to initial partial activation of the ERα enhancer for enhance priming. Maturation of the enhancer in turn switches the p300 recruitment mechanism to an SRC-dependent manner, resulting in the maximum enhancer activity and transcription outcomes. Thus, our results illustrate the role of SRC in enhancing the activity of primed enhancers. Furthermore, we show that forced recruitment of p300 to inactive enhancers establishes active enhancer marks and induces ERα-target gene expression. Together, we demonstrate the molecular mechanisms of ERα enhancer complex formation where p300 plays a pivotal role in enhancer activation and target gene expression controlled by distinctive mechanisms through different stages of ERα enhancer complex formation.

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The histone variant H2A.Z is an important regulator of enhancer activity.

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