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Title: SRC-2 is an essential coactivator for orchastrating metabolism and circadian rhythm

item STASHI, ERIN - Baylor College Of Medicine
item LANZ, RAINER - Baylor College Of Medicine
item MAO, JIANQIANG - Baylor College Of Medicine
item MICHAILIDIS, GEORGE - University Of Michigan
item ZHU, BOKAI - Baylor College Of Medicine
item KETTNER, NICOLE - Children'S Nutrition Research Center (CNRC)
item PUTLURI, NAGIREDDY - Baylor College Of Medicine
item REINEKE, ERIN - Baylor College Of Medicine
item REINEKE, LUCAS - Baylor College Of Medicine
item DASGUPTA, SUBHAMOY - Baylor College Of Medicine
item DEAN, ADAM - Baylor College Of Medicine
item STEVENSON, CONNOR - Trinity University
item NATARAJAN, SIVASUBRAMANIAN - Baylor College Of Medicine
item SREEKUMAR, ARUN - Baylor College Of Medicine
item DEMAYO, FRANCESCO - Baylor College Of Medicine
item YORK, BRIAN - Baylor College Of Medicine
item FU, LONING - Children'S Nutrition Research Center (CNRC)
item O'MALLEY, BERT - Baylor College Of Medicine

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/15/2013
Publication Date: 2/1/2014
Citation: 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., Natarajan, S., Sreekumar, A., Demayo, F., York, B., Fu, L., O'Malley, B.W. 2014. SRC-2 is an essential coactivator for orchastrating metabolism and circadian rhythm. Cell Reports. 6(4):633-645.

Interpretive Summary: Disruption of circadian homeostasis, a mechanism controlling our rest/awake cycles over a 24 hour period, has reached epidemic levels in the United States. The majority of Americans sleeps less than their ancestors on an average day and also oscillates between under-sleeping on work days and over-sleeping on free-days throughout their school and working lives, a phenomenon called "social jet-lag". In addition, about 80% of the working population in the U.S. relies on alarm clocks to wake up to meet their daily working schedules, and that teenagers that show most obvious increase in the risk of obesity display a larger scale of social jet-lag than adults. Researchers found that every one hour of chronic social jet-lag increased the risk of overweight or obesity by 33%. Therefore, understanding the mechanism of social jet-lag is important for finding a solution to treat obesity and obesity-related diseases. Circadian rhythm is controlled by an internal clock but not the light cues from the Sun. The clock is operated by circadian genes. One of the mechanisms for the clock to prevent obesity is to generate a 24 hour rhythm in gene expression in vivo. The study by Stashi et al discovered a novel function for SRC2, a protein previously known for its role in regulating gene expression, as a novel component in the circadian clock. SRC-2 is involved in controlling the length of a circadian period. Mice lacking SRC-2 show variable length of circadian period, which generate an effect like "social jet-lag" in humans. SRC-2 mutant mice showed lack of circadian homeostasis of metabolism in the liver, heart and fat tissues, leading to the development of metabolic syndromes and abnormal body weight. Therefore, SRC2 is potentially a novel therapeutic target for treating social jet-lag induced metabolic disorders in humans.

Technical 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.