SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm

Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1:CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circadian clock. [Display omitted] •SRC-2 cistromic analysis unveils circadian rhythm and metabolism-related functions•SRC-2 is a transcriptional coactivator for BMAL1:CLOCK•Ablation of SRC-2 disrupts the central clock•Loss of SRC-2 causes temporal shifts in the transcriptome and metabolome Steroid receptor coactivator 2 (SRC-2) has previously been identified as a major coregulator of energy homeostasis. Here, O’Malley and colleagues show that SRC-2 has a more overarching effect on systemic metabolism by serving as a coregulator in circadian rhythm. They identify a significant overlap between the BMAL1 and SRC-2 cistromes and show SRC-2 to be a transcriptional coactivator of BMAL1. These data strongly suggest that SRC-2 works to synchronize whole-body metabolism with circadian rhythm.