Interplay between Genetic Variation and Nutrition Challenge Controls Hepatic Diurnal Rhythms [ChIP-seq]

Variation in diurnal rhythms contributes to the risk of multiple diseases, yet the genomic and epigenomic basis remains largely unknown. Here, we show that SNPs in enhancer and promoter regions genome-wide contribute to variations in human diurnal rhythms. Differential rhythmic gene expression and physiological responses to diet-induced obesity in mice with different genetic backgrounds are linked to time-dependent enhancer-promoter interactions (EPI) regulated by cis-regulatory SNPs and transcription factors (TFs) like ESRRγ. Hepatocyte-specific Esrrγ knockout alters rhythmic processes in liver, including triglyceride synthesis and lipid droplet formation, across mouse strains. Moreover, motifs of ESRRγ and other lipid metabolism-related TFs are enriched in individual-specific EPIs harboring SNPs to control rhythmic genes in patients with MAFLD. SNPs located in these sites are correlated with hepatic metabolic traits. Thus, SNPs and TFs interdependently form the genomic and epigenomic basis for diurnal rhythm variation, contributing to disease risk.