Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude via REV-ERB Loading

Bokai Zhu, Leah A. Gates, Erin Stashi, Subhamoy Dasgupta, Naomi Gonzales, Adam Dean, Clifford C. Dacso, Brian York, Bert W. O'Malley

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

A central mechanism for controlling circadian gene amplitude remains elusive. We present evidence for a "facilitated repression (FR)" model that functions as an amplitude rheostat for circadian gene oscillation. We demonstrate that ROR and/or BMAL1 promote global chromatin decondensation during the activation phase of the circadian cycle to actively facilitate REV-ERB loading for repression of circadian gene expression. Mechanistically, we found that SRC-2 dictates global circadian chromatin remodeling through spatial and temporal recruitment of PBAF members of the SWI/SNF complex to facilitate loading of REV-ERB in the hepatic genome. Mathematical modeling highlights how the FR model sustains proper circadian rhythm despite fluctuations of REV-ERB levels. Our study not only reveals a mechanism for active communication between the positive and negative limbs of the circadian transcriptional loop but also establishes the concept that clock transcription factor binding dynamics is perhaps a central tenet for fine-tuning circadian rhythm. It has long been thought that the competitive binding of ROR and REV-ERB to ROR response element was responsible for the establishment of circadian rhythmicity. Zhu et al. propose an alternative "facilitated repression" model demonstrating that ROR promotes REV-ERB loading via modulating chromatin accessibility oscillation in an SRC-2/PBAF-dependent manner.

Original languageEnglish (US)
Pages (from-to)769-783
Number of pages15
JournalMolecular cell
Volume60
Issue number5
DOIs
StatePublished - Dec 3 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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