TY - JOUR
T1 - Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding
AU - McDowell, Ian C.
AU - Barrera, Alejandro
AU - D’Ippolito, Anthony M.
AU - Vockley, Christopher M.
AU - Hong, Linda K.
AU - Leichter, Sarah M.
AU - Bartelt, Luke C.
AU - Majoros, William H.
AU - Song, Lingyun
AU - Safi, Alexias
AU - Koçak, D. Dewran
AU - Gersbach, Charles A.
AU - Hartemink, Alexander J.
AU - Crawford, Gregory E.
AU - Engelhardt, Barbara E.
AU - Reddy, Timothy E.
N1 - Funding Information:
We thank the ENCODE DCC staff, especially I. Gabdank, C. Sloan, and A. Narayanan, for help in facilitating pipeline documentation and data release through the ENCODE project portal. We thank T. Konneker (NCSU), D.L. Aylor (NCSU), and C. Frank (formerly Duke) for contributing a custom script used to remove DNase-seq PCR artifacts. This work was mainly carried out at the Duke Center for Genomic and Computational Biology. This work was funded by the following grants: National Institutes of Health (NIH) U01 HG007900 (all authors), NIH F31 AI124563 (A.M.D.), NIH F31 HL129743 (C.M.V.), NIH R01 GM118551 (A.J.H.), NIH R01 DA036865 (D.D.K. and C.A.G.), NIH R00 HG006265 (B.E.E.), NIH R01 MH101822 (B.E.E.), and a Sloan Faculty Fellowship (B.E.E.).
Publisher Copyright:
© 2018 McDowell et al.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
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U2 - 10.1101/gr.233346.117
DO - 10.1101/gr.233346.117
M3 - Article
C2 - 30097539
AN - SCOPUS:85052747762
SN - 1088-9051
VL - 28
SP - 1272
EP - 1284
JO - Genome Research
JF - Genome Research
IS - 9
ER -