Journal article
Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism
Cell metabolism, Vol.37(10), pp.1961-1979.e7
10/07/2025
DOI: 10.1016/j.cmet.2025.07.010
PMID: 40858101
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.
[Display omitted]
•Genetic variants contribute to variation in peripheral diurnal rhythms•More than 80% of rhythmic genes and E-PIs are interdependent on genetics and nutrition•Noncanonical clock regulators govern rhythmic expression, lipid droplets, and metabolism•Human SNPs linked to rhythmic gene expression are tightly associated with metabolic traits
Noncanonical clock regulators bridge genetics and nutrition to mediate 3D enhancer-promoter interactions, contributing to diurnal rhythm variation and metabolic disease risk.
Details
- Title: Subtitle
- Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism
- Creators
- Dishu Zhou - Xiamen UniversityYing Chen - Baylor College of MedicinePanpan Liu - Baylor College of MedicineKun Zhu - University of PennsylvaniaJuliet Holder-Haynes - Baylor College of MedicineS. Julie-Ann Lloyd - Baylor College of MedicineCam Mong La - Baylor College of MedicineInna I. Astapova - Baylor College of MedicineSeunghee Choa - Baylor College of MedicineYing Xiong - Case Western Reserve UniversityHosung Bae - University of California, IrvineMarlene Aguilar - Children's Nutrition Research Center at Baylor College of MedicineHongyuan Yang - The University of Texas Health Science Center at HoustonYu A. An - The University of Texas Health Science CenterZheng Sun - Baylor College of MedicineMark A. Herman - Baylor College of MedicineXia Gao - Children's Nutrition Research Center at Baylor College of MedicineLiming Pei - Children's Hospital of PhiladelphiaCholsoon Jang - University of California, IrvineJoshua D. Rabinowitz - Princeton UniversitySamer G. Mattar - Baylor College of MedicineYongyou Zhang - Xiamen UniversityDongyin Guan - Baylor College of Medicine
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.37(10), pp.1961-1979.e7
- DOI
- 10.1016/j.cmet.2025.07.010
- PMID
- 40858101
- NLM abbreviation
- Cell Metab
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 10/07/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217034702771
Metrics
1 Record Views