title: SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm.
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.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Erin
authors: E
authors: Stashi
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Rainer B
authors: RB
authors: Lanz
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Jianqiang
authors: J
authors: Mao
authors: 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.
authors: George
authors: G
authors: Michailidis
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Bokai
authors: B
authors: Zhu
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Nicole M
authors: NM
authors: Kettner
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Nagireddy
authors: N
authors: Putluri
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Erin L
authors: EL
authors: Reineke
authors: Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza Houston, TX 77030, USA.
authors: Lucas C
authors: LC
authors: Reineke
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Subhamoy
authors: S
authors: Dasgupta
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Adam
authors: A
authors: Dean
authors: Department of Biochemistry and Molecular Biology, Trinity University, One Trinity Place, San Antonio, TX 78212-7200, USA.
authors: Connor R
authors: CR
authors: Stevenson
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Natarajan
authors: N
authors: Sivasubramanian
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Arun
authors: A
authors: Sreekumar
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Francesco
authors: F
authors: Demayo
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Brian
authors: B
authors: York
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Loning
authors: L
authors: Fu
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: berto@bcm.edu.
authors: Bert W
authors: BW
authors: O'Malley
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D008099:Liver / Q000378:metabolism; D008297:Male; D055442:Metabolome; D051379:Mice; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D059467:Transcriptome
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D056926:CLOCK Proteins; C538944:Clock protein, mouse