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Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12305-E12312. doi: 10.1073/pnas.1816411115. Epub 2018 Dec 10.

Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks.

Author information

1
Keck School of Medicine, University of Southern California, Los Angeles, CA 90089.
2
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
3
Institute of Transformative Bio-Molecules, Nagoya University, 464-8602 Nagoya, Japan.
4
Keck School of Medicine, University of Southern California, Los Angeles, CA 90089; stevekay@usc.edu.

Abstract

Either expression level or transcriptional activity of various nuclear receptors (NRs) have been demonstrated to be under circadian control. With a few exceptions, little is known about the roles of NRs as direct regulators of the circadian circuitry. Here we show that the nuclear receptor HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer. We define a central role for HNF4A in maintaining cell-autonomous circadian oscillations in a tissue-specific manner in liver and colon cells. Not only transcript level but also genome-wide chromosome binding of HNF4A is rhythmically regulated in the mouse liver. ChIP-seq analyses revealed cooccupancy of HNF4A and CLOCK:BMAL1 at a wide array of metabolic genes involved in lipid, glucose, and amino acid homeostasis. Taken together, we establish that HNF4A defines a feedback loop in tissue-specific mammalian oscillators and demonstrate its recruitment in the circadian regulation of metabolic pathways.

KEYWORDS:

CLOCK:BMAL1; HNF4A; circadian rhythm; nuclear receptor; transrepression

PMID:
30530698
PMCID:
PMC6310821
DOI:
10.1073/pnas.1816411115
[Indexed for MEDLINE]
Free PMC Article

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