Actin cytoskeleton signaling via MRTF/SRF entrains circadian clock

Abstract

The circadian clock is entrained to daily environmental cues. Integrin-linked intracellular signaling via actin cytoskeleton dynamics transduces extracellular matrix interactions to Myocardin-related Transcription Factor (MRTF)/Serum Response Factor (SRF)-mediated transcription. Actin cytoskeleton organization in liver displays diurnal oscillations and SRF-MRTF activity exert transcriptional control to entrain clock. By interrogating disparate upstream events involved in actin cytoskeleton-MRTF-A/SRF signaling cascade, here we show that this signaling cascade transduce cellular niche cues to modulate circadian clock function. Pharmacological inhibitions of MRTF-A/SRF, by disrupting actin polymerization or blocking ROCK kinase, induced period lengthening with augmented clock amplitude, and genetic loss-of-functions of Srf or Mrtf-a mimic that of actin-depolymerizing agents. In contrast, actin-polymerization induced by Jasplakinolide shortened period with attenuated amplitude. In addition, interfering with cell-matrix interaction through blockade of integrin, inhibition of focal adhesion kinase or attenuating matrix rigidity led to reduced period length while enhancing amplitude. Mechanistically, we identify that core clock repressors, Per2, Nr1d1, and Nfil3, are direct transcriptional targets of MRTF-A/SRF in mediating actin dynamic-induced clock response. Collectively, our findings defined an integrin-actin cytoskeleton-MRTF/SRF pathway in linking clock entrainment with extracellular microenvironment that may facilitate cellular adaptation to its physical niche. Summary statementOur study revealed the role of actin cytoskeleton-MRTF/SRF signaling in entraining circadian clock to its extracellular physical niche environment.