TY - JOUR
T1 - Chemical perturbations reveal that RUVBL2 regulates the circadian phase in mammals
AU - Ju, Dapeng
AU - Zhang, Wei
AU - Yan, Jiawei
AU - Zhao, Haijiao
AU - Li, Wei
AU - Wang, Jiawen
AU - Liao, Meimei
AU - Xu, Zhancong
AU - Wang, Zhiqiang
AU - Zhou, Guanshen
AU - Mei, Long
AU - Hou, Nannan
AU - Ying, Shuhua
AU - Cai, Tao
AU - Chen, She
AU - Xie, Xiaowen
AU - Lai, Luhua
AU - Tang, Chao
AU - Park, Noheon
AU - Takahashi, Joseph S.
AU - Huang, Niu
AU - Qi, Xiangbing
AU - Zhang, Eric Erquan
N1 - Publisher Copyright:
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2020/5/6
Y1 - 2020/5/6
N2 - 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.
AB - 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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U2 - 10.1126/SCITRANSLMED.ABA0769
DO - 10.1126/SCITRANSLMED.ABA0769
M3 - Article
C2 - 32376767
AN - SCOPUS:85084383389
SN - 1946-6234
VL - 12
JO - Science translational medicine
JF - Science translational medicine
IS - 542
M1 - eaba0769
ER -