GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock

Science. 2015 Jun 26;348(6242):1488-92. doi: 10.1126/science.aab3021. Epub 2015 Jun 4.

Abstract

Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbα modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbα to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbα regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erbα and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erbα uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.

Publication types

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

MeSH terms

  • Animals
  • CLOCK Proteins / genetics*
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics*
  • Gene Expression Regulation*
  • Hepatocyte Nuclear Factor 6 / metabolism
  • Histone Deacetylases / metabolism*
  • Lipid Metabolism / genetics
  • Liver / metabolism
  • Male
  • Metabolism / genetics*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
  • Organ Specificity
  • Protein Binding
  • Tissue Distribution

Substances

  • Hepatocyte Nuclear Factor 6
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Onecut1 protein, mouse
  • CLOCK Proteins
  • Histone Deacetylases
  • histone deacetylase 3

Associated data

  • GEO/GSE67973