Cell Reports
Volume 6, Issue 4, 27 February 2014, Pages 633-645
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Article
SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm

https://doi.org/10.1016/j.celrep.2014.01.027Get rights and content
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Highlights

  • SRC-2 cistromic analysis unveils circadian rhythm and metabolism-related functions

  • SRC-2 is a transcriptional coactivator for BMAL1:CLOCK

  • Ablation of SRC-2 disrupts the central clock

  • Loss of SRC-2 causes temporal shifts in the transcriptome and metabolome

Summary

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.

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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These authors contributed equally to this work