Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock

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Science  26 Jun 2015:
Vol. 348, Issue 6242, pp. 1488-1492
DOI: 10.1126/science.aab3021

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Multitasking around the clock

Chronic disruption of our circadian rhythms—for example, through shift work—may increase the risk of metabolic disease. Zhang et al. found that a multitasking transcription factor called Rev-erb-α regulates expression of both clock and metabolic genes through distinct mechanisms. At clock genes, it binds directly to a specific DNA sequence, displacing a competing transcription factor. At metabolic genes, it interacts not with DNA but with other transcription factors that regulate metabolic gene expression in a tissue-specific manner.

Science, this issue p. 1488


Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbα modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbα to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbα regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type–specific transcription factors. Thus, direct competition between Rev-erbα and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erbα uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.

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