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

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...

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Bibliographic Details
Published in:Molecular cell 2015-12, Vol.60 (5), p.769-783
Main Authors: Zhu, Bokai, Gates, Leah A., Stashi, Erin, Dasgupta, Subhamoy, Gonzales, Naomi, Dean, Adam, Dacso, Clifford C., York, Brian, O’Malley, Bert W.
Format: Article
Language:English
Subjects:
Animals
ARNTL Transcription Factors - metabolism
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
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Summary: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. [Display omitted] •SRC-2 stabilizes RORα binding on nucleosomal DNA at CT22 of the diurnal cycle•REV-ERBs preferentially bind to open chromatin at CT10 of the diurnal cycle•SRC-2/PBAF mediates chromatin accessibility oscillation to assist REV-ERB loading•The facilitated repression model functions as amplitude rheostat for cycling genes 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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2015.10.024