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Ep300 sequestration to functionally distinct glucocorticoid receptor binding loci underlie rapid gene activation and repression

ABSTRACT: The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets. We show that the chromatin interaction networks of GR-activated and repressed genes are spatially separated and vary in the features and configuration of their GBS and other non-GBS regulatory elements. The convergence of the KLF4 pathway in GR-activated domains and the STAT6 pathway in GR-repressed domains, impose opposite transcriptional effects to GR, independent of hormone application. Moreover, the ROR and Rev-erb transcription factors serve as positive and negative regulators, respectively, of GR-mediated gene activation. We found that the spatial crosstalk between GBSs and non-GBSs provides a physical platform for sequestering the Ep300 co-activator from non-GR regulatory loci in both GR-activated and -repressed gene compartments. While this allows rapid gene repression, Ep300 recruitment to GBSs is productive specifically in the activated compartments, thus providing the basis for gene induction.

ORGANISM(S): Mus musculus

PROVIDER: GSE106209 | GEO | 2020/10/31

REPOSITORIES: GEO

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Ep300 sequestration to functionally distinct glucocorticoid receptor binding loci underlie rapid gene activation and repression

Project description:The transcription factor glucocorticoid receptor (GR) is a key mediator of stress response and a broad range of physiological processes. How can GR rapidly activate the expression of some genes while repress others, remains an open question due to the challenge to associate GR binding sites (GBSs) to their distant gene targets. Mapping the 3D scope of GR-responsive promoters using high-resolution 4C-seq unravelled spatial separation between chromatin interaction networks of GR-activated and repressed genes. The spatial compartments of GR-activated and GR-repressed genes vary in the types and configuration of their residing regulatory elements. GR binding to chromatin sequester the co-activator Ep300 from non-GR regulatory loci in GR-activated and repressed gene compartments. While this allows rapid gene repression, effective Ep300 recruitment to GR binding sites positioned within the activated compartments provide the basis for gene induction. Moreover, focused analysis on GBS together with other regulatory loci that cluster in the GR activated compartments identifies ROR, Rev-erb, and Klf4 transcription factors as co-regulators for GR-mediated gene expression. Thus spatial crosstalk between various regulatory loci in GR-responsive compartments provides the basis for precise transcriptional response

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