Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
Department of Botany and Plant Sciences, University of California, Riverside, CA, 92521, USA.
Nat Commun. 2021 Nov 3;12(1):6350. doi: 10.1038/s41467-021-26567-3.
Transcription modulated by the circadian clock is diverse across cell types, underlying circadian control of peripheral metabolism and its observed perturbation in human diseases. We report that knockout of the lineage-specifying Hnf4a gene in mouse liver causes associated reductions in the genome-wide distribution of core clock component BMAL1 and accessible chromatin marks (H3K4me1 and H3K27ac). Ectopically expressing HNF4A remodels chromatin landscape and nucleates distinct tissue-specific BMAL1 chromatin binding events, predominantly in enhancer regions. Circadian rhythms are disturbed in Hnf4a knockout liver and HNF4A-MODY diabetic model cells. Additionally, the epigenetic state and accessibility of the liver genome dynamically change throughout the day, synchronized with chromatin occupancy of HNF4A and clustered expression of circadian outputs. Lastly, Bmal1 knockout attenuates HNF4A genome-wide binding in the liver, likely due to downregulated Hnf4a transcription. Our results may provide a general mechanism for establishing circadian rhythm heterogeneity during development and disease progression, governed by chromatin structure.
转录受生物钟调节，在不同细胞类型中具有多样性，这是生物钟对周围代谢的控制及其在人类疾病中观察到的紊乱的基础。我们报告称，敲除小鼠肝脏中谱系特异性 Hnf4a 基因会导致核心时钟组件 BMAL1 和可及染色质标记（H3K4me1 和 H3K27ac）的全基因组分布相关减少。异位表达 HNF4A 重塑染色质景观，并引发独特的组织特异性 BMAL1 染色质结合事件，主要发生在增强子区域。Hnf4a 敲除肝和 HNF4A-MODY 糖尿病模型细胞中的生物钟节律紊乱。此外，肝脏基因组的表观遗传状态和可及性在一天中动态变化，与 HNF4A 的染色质占据和生物钟输出的簇状表达同步。最后，Bmal1 敲除减弱了肝脏中 Bmal1 的全基因组结合，可能是由于 Hnf4a 转录下调。我们的研究结果可能为在发育和疾病进展过程中建立生物钟节律异质性提供了一个普遍的机制，该机制受染色质结构的控制。
