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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ARNTL Transcription Factors / chemistry
  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • CLOCK Proteins / chemistry
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism*
  • Cell Line
  • Circadian Rhythm*
  • Colon / metabolism
  • Dimerization
  • Down-Regulation
  • Gene Expression Regulation
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Humans
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Organ Specificity
  • Transcription, Genetic


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • CLOCK Proteins
  • Clock protein, mouse