1. Academic Validation
  2. CDK9 modulates circadian clock by attenuating REV-ERBα activity

CDK9 modulates circadian clock by attenuating REV-ERBα activity

  • Biochem Biophys Res Commun. 2019 Jun 11;513(4):967-973. doi: 10.1016/j.bbrc.2019.04.043.
Jiali Ou 1 Huilin Li 1 Peiyuan Qiu 2 Qing Li 2 Hung-Chun Chang 2 Yun-Chi Tang 3
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 3 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. Electronic address: [email protected]
Abstract

Circadian clock and cell cycle are vital cellular programs acting in a timely-regulated, cyclic manner. The two cellular oscillators are coupled in various ways to facilitate biological processes. Here we report CDK9, a kinase belongs to the CDK family in regulating cell cycle and RNA Pol II activity, can serve as a modulator for circadian clock. We identified CDK Inhibitor LY2857785 potently blocked PER2:LUC expression in MEFs from a screen of 17 commonly-used CDK inhibitors. We further analyzed the possible targets of LY2857785 by siRNA approach, and confirmed CDK9 as the main effector. LY2857785 treatment, as well as CDK9 knock-down, led to lowered expression of Bmal1 in accordance with elevated expression of Rev-Erbα. CDK9 associated with REV-ERBα thus attenuated REV-ERBα binding to the RORE for Bmal1 suppression. To conform the circadian-modulating activity of CDK9 in vivo, we knocked down CDK9 in mice at the anterior hypothalamus covering the central oscillator SCN, and found the respiratory exchange ratio, daily activity and circadian period were altered in the Cdk9-knockdown mice. Together, our finding designated CDK9 as a novel modulator in circadian clock. CDK9 may serve as a vital basis to understand circadian- and cell cycle-misregulated ailments such as Cancer.

Keywords

BMAL1; CDK9; Circadian clock; PER2; REV-ERBa; Suprachiasmatic nucleus.

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