美国贝勒医学院Dongyin Guan小组的研究发现遗传-营养相互作用控制增强子-启动子动态和肝脏脂质代谢。相关论文于2025年8月25日发表在《细胞—代谢》杂志上。

课题组发现遗传变异导致人类和小鼠肝脏基因表达的不同昼夜模式。营养挑战以一种菌株特异性的方式改变同源性肝脏基因表达的节律性。值得注意的是，遗传和营养相互依赖地控制着超过80%的节律性基因和增强子-启动子相互作用（E-PIs），其中非规范时钟调节因子雌激素相关受体γ (ESRRγ)在基序挖掘过程中成为顶级转录因子。敲除Esrrγ可以消除小鼠对饮食的特异性代谢过程，而与节律性基因表达相关的单核苷酸多态性（SNPs）在脂肪变性人肝脏的E-PIs中富集，并与脂质代谢特征相关。这些发现揭示了以前未被充分认识的遗传-环境相互作用在调节脂质代谢特征中的时间方面，对肥胖相关疾病易感性和个性化时间治疗的个体差异具有启示意义。

据介绍，生物钟控制着24小时的节律过程。然而，生物钟基因之外的遗传变异如何影响外周昼夜节律在很大程度上仍然未知。

附：英文原文

Title: Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism

Author: 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

Issue&Volume: 2025-08-25

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.

DOI: 10.1016/j.cmet.2025.07.010

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00356-0