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Multimodal regulatory elements within a hormone-specific super enhancer control a heterogeneous transcriptional response.

ABSTRACT: 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 investigated 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, 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 contribute to hormone-induced transcriptional heterogeneity and demonstrate the potential for targeted modulation of oncogene expression.

SUBMITTER: Hoffman JA

PROVIDER: S-EPMC8897972 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Multimodal regulatory elements within a hormone-specific super enhancer control a heterogeneous transcriptional response.

Hoffman Jackson A JA Trotter Kevin W KW Day Christopher R CR Ward James M JM Inoue Kaoru K Rodriguez Joseph J Archer Trevor K TK

Molecular cell 20220124 4

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 investigated 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-d ...[more]

PMID: 35077705

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Multimodal regulatory elements within a hormone-specific super enhancer control a heterogeneous transcriptional response.

Publications

Multimodal regulatory elements within a hormone-specific super enhancer control a heterogeneous transcriptional response.

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