SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm
Stashi, E.;Lanz, R. B.;Mao, J.;Michailidis, G.;Zhu, B.;Kettner, N. M.;Putluri, N.;Reineke, E. L.;Reineke, L. C.;Dasgupta, S.;Dean, A.;Stevenson, C. R.;Sivasubramanian, N.;Sreekumar, A.;Demayo, F.;York, B.;Fu, L.;O'Malley, B. W. (2014). "SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm." Cell Reports 6 4: 633-45
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.
ISSN: 2211-1247 (Electronic)
Accession Number: 24529706