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Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription

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Science  16 Mar 2018:
Vol. 359, Issue 6381, pp. 1274-1277
DOI: 10.1126/science.aao6891

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Chromosome dynamics and cellular clocks

Many genes undergo daily or circadian changes in their rate of transcription. Kim et al. explored the mechanism by which the circadian clock is linked to chromosome dynamics (see the Perspective by Diettrich Mallet de Lima and Göndör). They used a chromosome conformation capture technique (Hi-C) to identify the interactions of adjacent DNA fragments and determine how DNA looping that altered such interactions changed over daily cycles. The repressive transcription factor Rev-erbα, which functions as part of the mammalian clock mechanism, appears to bind to chromatin and recruit a protein complex that evicts other proteins that enhance looping, thus favoring enhancer-promoter interactions.

Science, this issue p. 1274; see also p. 1212

Abstract

Mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors that constitute molecular clocks. Core clock transcription factors bind to the genome at enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. We found that in mice, circadian gene expression in the liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erbα, a core repressive transcription factor of the clock, opposes functional loop formation between Rev-erbα–regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 co-repressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. Thus, a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene transcription.

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