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

Mol Cell. 2015 Dec 3;60(5):769-783. doi: 10.1016/j.molcel.2015.10.024. Epub 2015 Nov 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / metabolism
  • Animals
  • Chromatin / metabolism*
  • Circadian Rhythm*
  • Gene Expression Regulation
  • Liver / metabolism*
  • Mice
  • Models, Biological
  • Nuclear Receptor Coactivator 2 / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Chromatin
  • Nr1d1 protein, mouse
  • Nuclear Receptor Coactivator 2
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Rora protein, mouse

Associated data

  • GEO/GSE67860