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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Rhythm*
  • Liver / metabolism
  • Male
  • Metabolome*
  • Mice
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / metabolism*
  • Organ Specificity
  • Transcriptome

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Nuclear Receptor Coactivator 2
  • CLOCK Proteins
  • Clock protein, mouse

Associated data

  • GEO/GSE53039