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

• Main Authors: Erin Stashi, Rainer B. Lanz, Jianqiang Mao, George Michailidis, Bokai Zhu, Nicole M. Kettner, Nagireddy Putluri, Erin L. Reineke, Lucas C. Reineke, Subhamoy Dasgupta, Adam Dean, Connor R. Stevenson, Natarajan Sivasubramanian, Arun Sreekumar, Francesco DeMayo, Brian York, Loning Fu, Bert W. O’Malley
• Format: Article
• Language: English
• Published: Elsevier 2014-02-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124714000448

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.