NR5A2 controls gene expression and chromatin contacts of essential circadian metabolic genes in the liver

Although rhythmic chromatin looping has been described in the liver, the transcription factors that mediate these temporal interactions remain poorly defined. Here, we identify the nuclear receptor NR5A2 as a key regulator of circadian enhancer–promoter communication in the mouse liver.

We show that NR5A2 protein levels fluctuate over the 24-hour cycle, peaking around Zeitgeber time 0 (ZT0). Genome-wide analysis reveals that NR5A2 preferentially binds H3K27ac-enriched enhancer regions, many of which engage in chromatin looping with promoters of metabolic genes. High-resolution 4C-seq analyses demonstrate that promoters of Elovl5 and Ppp1r3c dynamically interact with NR5A2- and H3K27ac-enriched enhancers in a time-dependent manner, with maximal interactions at ZT0 and reduced contacts at ZT12.