Discrete Functions Of Nuclear Receptor Rev-Erb Alpha Couple Metabolism To The Clock

Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erb alpha, 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-erba modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erba to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erba 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-erba and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erba uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.