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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 52; pp. E12305 - E12312
• Main Authors: Qu, Meng, Duffy, Tomas, Hirota, Tsuyoshi, Kay, Steve A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.12.2018
• Series: PNAS Plus
• Subjects: Amino acids; Animals; ARNTL Transcription Factors - chemistry; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Biological Sciences; BMAL1 protein; Cell Line; Cells; Chromosomes; Circadian Rhythm; Circadian rhythms; Circuits; CLOCK Proteins - chemistry; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Colon; Colon - metabolism; Control theory; Dimerization; Down-Regulation; Feedback loops; Gene Expression Regulation; Genes; Genomes; Glucose; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Hepatocytes; Homeostasis; Humans; Lipids; Liver; Liver - metabolism; Male; Metabolic pathways; Mice; Mice, Inbred C57BL; Nuclear receptors; Organ Specificity; Oscillators; PNAS Plus; Receptors; Regulators; Transcription; Transcription, Genetic; CLOCK:BMAL1; transrepression; nuclear receptor; HNF4A; circadian rhythm
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1816411115

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.