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Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

Author(s): McDowell, Ian C; Barrera, Alejandro; D'Ippolito, Anthony M; Vockley, Christopher M; Hong, Linda K; et al

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Abstract: Glucocorticoids are potent steroid hormones that regulate immunity and metabolism by activating the transcription factor (TF) activity of glucocorticoid receptor (GR). Previous models have proposed that DNA binding motifs and sites of chromatin accessibility predetermine GR binding and activity. However, there are vast excesses of both features relative to the number of GR binding sites. Thus, these features alone are unlikely to account for the specificity of GR binding and activity. To identify genomic and epigenetic contributions to GR binding specificity and the downstream changes resultant from GR binding, we performed hundreds of genome-wide measurements of TF binding, epigenetic state, and gene expression across a 12-h time course of glucocorticoid exposure. We found that glucocorticoid treatment induces GR to bind to nearly all pre-established enhancers within minutes. However, GR binds to only a small fraction of the set of accessible sites that lack enhancer marks. Once GR is bound to enhancers, a combination of enhancer motif composition and interactions between enhancers then determines the strength and persistence of GR binding, which consequently correlates with dramatic shifts in enhancer activation. Over the course of several hours, highly coordinated changes in TF binding and histone modification occupancy occur specifically within enhancers, and these changes correlate with changes in the expression of nearby genes. Following GR binding, changes in the binding of other TFs precede changes in chromatin accessibility, suggesting that other TFs are also sensitive to genomic features beyond that of accessibility.
Publication Date: 2018
Citation: McDowell, Ian C., Alejandro Barrera, Anthony M. D'Ippolito, Christopher M. Vockley, Linda K. Hong, Sarah M. Leichter, Luke C. Bartelt, William H. Majoros, Lingyun Song, Alexias Safi, D. Dewran Koçak, Charles A. Gersbach, Alexander J. Hartemink, Gregory E. Crawford, Barbara E. Engelhardt, and Timothy E. Reddy. "Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding." Genome Research 28, no. 9 (2018): pp. 1272-1284. doi:10.1101/gr.233346.117
DOI: 10.1101/gr.233346.117
ISSN: 1088-9051
EISSN: 1549-5469
Pages: 1272 - 1284
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Genome Research
Version: Final published version. This is an open access article.

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