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Cell Rep. 2014 Feb 27;6(4):633-45. doi: 10.1016/j.celrep.2014.01.027. Epub 2014 Feb 13.

SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm.

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
2
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Statistics, University of Michigan, 500 South State Street, Ann Arbor, MI 48109, USA.
3
Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza Houston, TX 77030, USA.
4
Department of Biochemistry and Molecular Biology, Trinity University, One Trinity Place, San Antonio, TX 78212-7200, USA.
5
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: berto@bcm.edu.

Abstract

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.

PMID:
24529706
PMCID:
PMC4096300
DOI:
10.1016/j.celrep.2014.01.027
[Indexed for MEDLINE]
Free PMC Article

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