Genetics-Nutrition Interactions Control Diurnal Enhancer-Promoter Dynamics and Liver Lipid Metabolism

Authors

• Dishu Zhou
• Ying Chen
• Panpan Liu
• Kun Zhu
• Juliet Holder-Haynes
• S Julie-Ann Lloyd
• Cam Mong La
• Inna I Astapova
• Seunghee Choa
• Ying Xiong
• Hosung Bae
• Marlene Aguilar
• Hongyuan Yang
• Yu A An
• Zheng Sun
• Mark A Herman
• Xia Gao
• Liming Pei
• Cholsoon Jang
• Joshua D Rabinowitz
• Samer G Mattar
• Yongyou Zhang
• Dongyin Guan

Language

English

Publication Date

10-7-2025

Journal

Cell Metabolism

DOI

10.1016/j.cmet.2025.07.010

PMID

40858101

PMCID

PMC12923262

PubMedCentral® Posted Date

4-28-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to diet in mice, while single-nucleotide polymorphisms (SNPs) associated with rhythmic gene expression are enriched in E-PIs in steatotic human livers and correlate with lipid metabolism traits. These findings reveal a previously underappreciated temporal aspect of genetics-environment interaction in regulating lipid metabolic traits, with implications for individual variations in obesity-associated disease susceptibility and personalized chronotherapy.

Keywords

Animals, Liver, Humans, Mice, Lipid Metabolism, Promoter Regions, Genetic, Circadian Rhythm, Polymorphism, Single Nucleotide, Male, Mice, Inbred C57BL, Enhancer Elements, Genetic, Mice, Knockout, Receptors, Estrogen, Female, Circadian Clocks, Diurnal rhythm, Genetic variation, 3D enhancer-promoter interaction, Metabolic disorders, Human metabolic traits

Published Open-Access

yes

Recommended Citation

Zhou, Dishu; Chen, Ying; Liu, Panpan; et al., "Genetics-Nutrition Interactions Control Diurnal Enhancer-Promoter Dynamics and Liver Lipid Metabolism" (2025). Faculty, Staff and Student Publications. 3926.
https://digitalcommons.library.tmc.edu/uthmed_docs/3926