PRC2- EZH1 contributes to circadian gene expression by orchestrating chromatin states and RNA polymerase II complex stability

Circadian rhythmicity of gene expression is a conserved feature of cell physiology. This involves fine-tuning between transcriptional and post-transcriptional mechanisms and strongly depends on the metabolic state of the cell. Together these processes guarantee an adaptive plasticity of tissue-specific genetic programs. However, it is unclear how the epigenome and RNA Pol II rhythmicity are integrated. Here we show that the PcG protein EZH1 has a gateway bridging function in post-mitotic skeletal muscle cells. On one hand, the circadian clock master regulator BMAL1 directly controls oscillatory behavior and periodic assembly of core components of the PRC2-EZH1 complex. On the other hand, EZH1 is essential for circadian gene expression at alternate Zeitgeber times, through stabilization of RNA Polymerase II preinitiation complexes, thereby controlling nascent transcription. Collectively, our data show that PRC2-EZH1 regulates circadian transcription both negatively and positively by modulating chromatin states and basal transcription complex stability.

基因表达的昼夜节律性是细胞生理的保守特征。该过程涉及转录与转录后调控机制间的精细平衡，且高度依赖细胞的代谢状态。上述过程共同保障了组织特异性基因程序的适应性可塑性。然而，目前尚不明确表观基因组与RNA聚合酶II（RNA Pol II）的节律性是如何实现整合的。本研究证实，多梳家族（PcG）蛋白EZH1在有丝分裂后骨骼肌细胞中发挥桥梁介导功能。一方面，生物钟核心调控因子BMAL1可直接调控PRC2-EZH1复合物核心组分的振荡行为与周期性组装；另一方面，EZH1可通过稳定RNA聚合酶II预起始复合物，在交替授时因子（Zeitgeber）周期下调控昼夜节律基因的表达，进而控制新生转录过程。综上，本研究数据表明，PRC2-EZH1复合物可通过调控染色质状态与基础转录复合物稳定性，实现对昼夜转录的双向（负向与正向）调控。