Format

Send to

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

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

Author information

1
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Molecular and Cellular Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
3
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. lazar@mail.med.upenn.edu.

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.

PMID:
26044300
PMCID:
PMC4613749
DOI:
10.1126/science.aab3021
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center