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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE193987 | GEO | 2022/05/29

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

2022-05-29 | GSE193986 | GEO

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

Project description: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.

2020-10-31 | GSE106209 | GEO

BRG1 governs Glucocorticoid Receptor interactions with chromatin and pioneer factors across the genome

Project description:The Glucocorticoid Receptor (GR) alters transcriptional activity in response to hormones by interacting with chromatin at GR binding sites (GBSs) throughout the genome. Our work in human breast cancer cells identifies three classes of GBSs with distinct epigenetic characteristics and reveals that BRG1 interacts with GBSs prior to hormone exposure. The GBSs pre-occupied by BRG1 are more accessible and transcriptionally active than other GBSs. BRG1 is required for a proper and robust transcriptional hormone response and knockdown of BRG1 blocks recruitment of the pioneer factors FOXA1 and GATA3 to GBSs. Finally, GR interaction with FOXA1 and GATA3 binding sites was restricted to sites pre-bound by BRG1. These findings demonstrate that BRG1 establishes specialized chromatin environments that define multiple classes of GBS. This in turn predicts that GR and other transcriptional activators function via multiple distinct chromatin-based mechanisms to modulate the transcriptional response.

2018-05-22 | GSE112491 | GEO

Glucocorticoid inducton of DDIT4 transcription

Project description:The hormone stimulated Glucocorticoid Receptor (GR) modulates transcription by interacting with thousands of enhancers and GR binding sites (GBSs) throughout the genome. Here, we examined the effects of GR binding on enhancer dynamics and interrogated the contributions of individual GBSs to the hormone response. Hormone treatment resulted in genome-wide reorganization of the enhancer landscape in breast cancer cells. Upstream of the DDIT4 oncogene, GR bound to four sites constituting a hormone-dependent super enhancer. Three GBSs were required as hormone-dependent enhancers that differentially promoted histone acetylation and transcription frequency and burst size. Conversely, the fourth site suppressed transcription and hormone treatment alleviated this suppression. GR binding within the super enhancer promoted a loop-switching mechanism that allowed interaction of the DDIT4 TSS with the active GBSs. The unique functions of each GR binding site contributed to hormone-induced transcriptional heterogeneity and demonstrate the potential for targeted modulation of oncogene expression.

2022-01-24 | GSE173798 | GEO

Direct GR binding sites potentiate clusters of TF binding across the human genome [6]

Project description:The glucocorticoid receptor (GR) binds the human genome at >10,000 sites, but only regulates the expression of hundreds of genes. To determine the functional effect of each site, we measured the glucocorticoid (GC) responsive activity of nearly all GR binding sites (GBSs) captured using chromatin immunoprecipitation (ChIP) in A549 cells. 13% of GBSs assayed had GC-induced activity. The responsive sites were defined by direct GR binding via a GC response element (GRE) and exclusively increased reporter- gene expression. Meanwhile, most GBSs lacked GC-induced reporter activity. The non-responsive sites had epigenetic features of steady state enhancers and clustered around direct GBSs. Together, our data support a model in which clusters of GBSs observed with ChIP-seq reflect interactions between direct and tethered GBSs over tens of kilobases. We further show that those interactions can synergistically modulate the activity of direct GBSs, and may therefore play a major role in driving gene activation in response to GCs.

2016-08-25 | GSE79429 | GEO

Direct GR binding sites potentiate clusters of TF binding across the human genome [5]

2016-08-25 | GSE79428 | GEO

Direct GR binding sites potentiate clusters of TF binding across the human genome

2016-08-25 | GSE77869 | GEO

Direct GR binding sites potentiate clusters of TF binding across the human genome [8]

2016-08-25 | GSE79431 | GEO