EZH1 Orchestrates Rhythmicity of Circadian Gene Expression Acting on Transcription Machinery Integrity

Circadian rhythmicity of gene expression is a conserved feature of cell physiology. This involves fine tuning between transcriptional and post-transcriptional molecular mechanisms, strongly dependent on the metabolic state of the cell, which guarantees adaptive plasticity of tissue-specific genetic programs. Dynamics of epigenome structure and epigenetic regulators support this plasticity. However, the intermingle between epigenome and RNA Pol II rhythmicity remains to be investigated. Here we identify the Polycomb group (PcG) protein EZH1 as a gateway bridging function regulating periodic alternation between chromatin mediated silencing and active transcription in post-mitotic skeletal muscle cells. We show that PRC2-EZH1 core components are under direct regulation of BMAL1, and show an oscillatory behavior and a regulated periodic assembly of PRC2-EZH1 complex. Instead at alternate Zeitgeber points, EZH1 becomes essential for circadian gene expression, through stabilization of RNA Pol II preinitiation complex controlling nascent transcription process. Collectively, our data show that EZH1 depending on the stoichiometry of its partners guarantees both negative and positive modulation of RNA Pol II activity, resulting in oscillatory transcription.

基因表达的昼夜节律性是细胞生理学的保守特征。该过程涉及转录与转录后分子机制间的精细调控，且高度依赖细胞的代谢状态，以此保障组织特异性遗传程序的适应性可塑性。表观基因组结构的动态变化与表观遗传调控因子共同支撑这一可塑性。然而，表观基因组与RNA聚合酶II（RNA Pol II）节律性之间的复杂互作仍有待研究。本研究鉴定出多梳家族（Polycomb group, PcG）蛋白EZH1作为桥接调控因子，可调控有丝分裂后骨骼肌细胞中染色质介导的基因沉默与活跃转录间的周期性交替。我们证实，PRC2-EZH1核心组分受脑和肌肉ARNT样蛋白1（BMAL1）的直接调控，并呈现出振荡行为与受调控的PRC2-EZH1复合物周期性组装过程。而在交替的授时因子（Zeitgeber）时间点，EZH1通过稳定RNA聚合酶II预起始复合物以调控新生转录过程，成为昼夜节律基因表达的必需因子。综上，本研究数据表明，EZH1可通过其结合伴侣的化学计量比，实现对RNA聚合酶II活性的双向调控，最终产生振荡性转录。