2. Academic Validation
  3. Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals

Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals

  • Sci Transl Med. 2020 May 6;12(542):eaba0769. doi: 10.1126/scitranslmed.aba0769.
Dapeng Ju 1 2,  Wei Zhang 3,  Jiawei Yan 4,  Haijiao Zhao 1,  Wei Li 3,  Jiawen Wang 1,  Meimei Liao 1 2,  Zhancong Xu 1,  Zhiqiang Wang 1,  Guanshen Zhou 1,  Long Mei 1 4,  Nannan Hou 1,  Shuhua Ying 1,  Tao Cai 1,  She Chen 1,  Xiaowen Xie 4 5,  Luhua Lai 5 6,  Chao Tang 5 7,  Noheon Park 8,  Joseph S Takahashi 8 9,  Niu Huang 1 10,  Xiangbing Qi 11 10,  Eric Erquan Zhang 11 10
Affiliations

Affiliations

  • 1 National Institute of Biological Sciences, Beijing 102206, China.
  • 2 College of Biological Sciences, China Agricultural University, Beijing 100193, China.
  • 3 RPXDs (Suzhou) Co. Ltd., Suzhou City, Jiangsu Province 215028, China.
  • 4 School of Life Sciences, Peking University, Beijing 100871, China.
  • 5 Center for Quantitative Biology, Peking University, Beijing 100871, China.
  • 6 College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 7 School of Physics and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 8 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
  • 9 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
  • 10 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
  • 11 National Institute of Biological Sciences, Beijing 102206, China. zhangerquan@nibs.ac.cn qixiangbing@nibs.ac.cn.
PMID: 32376767 DOI: 10.1126/scitranslmed.aba0769
Abstract

Transcriptional regulation lies at the core of the circadian clockwork, but how the clock-related transcription machinery controls the circadian phase is not understood. Here, we show both in human cells and in mice that RuvB-like ATPase 2 (RUVBL2) interacts with other known clock proteins on chromatin to regulate the circadian phase. Pharmacological perturbation of RUVBL2 with the adenosine analog compound cordycepin resulted in a rapid-onset 12-hour clock phase-shift phenotype at human cell, mouse tissue, and whole-animal live imaging levels. Using simple peripheral injection treatment, we found that cordycepin penetrated the blood-brain barrier and caused rapid entrainment of the circadian phase, facilitating reduced duration of recovery in a mouse jet-lag model. We solved a crystal structure for human RUVBL2 in complex with a physiological metabolite of cordycepin, and biochemical assays showed that cordycepin treatment caused disassembly of an interaction between RUVBL2 and the core clock component BMAL1. Moreover, we showed with spike-in ChIP-seq analysis and binding assays that cordycepin treatment caused disassembly of the circadian super-complex, which normally resides at E-box chromatin loci such as PER1, PER2, DBP, and NR1D1 Mathematical modeling supported that the observed type 0 phase shifts resulted from derepression of E-box clock gene transcription.

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