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
  • 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. [email protected] [email protected].
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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