Computational and experimental insights into the circadian effects of SIRT1

Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11643-11648. doi: 10.1073/pnas.1803410115. Epub 2018 Oct 22.

Abstract

The circadian clock orchestrates 24-h rhythms in physiology in most living organisms. At the molecular level, the dogma is that circadian oscillations are based on a negative transcriptional feedback loop. Recent studies found the NAD+-dependent histone deacetylase, SIRT1, directly regulates acetylation status of clock components and influences circadian amplitude in cells. While Nakahata et al. [Nakahata Y, Kaluzova M (2008) Cell 134:329-340] reported that loss of SIRT1 increases amplitude through BMAL1 acetylation, Asher et al. [Asher G, Gatfield D (2008) Cell 134:317-328] reported that loss of SIRT1 decreases amplitude through an increase in acetylated PER2. To address this SIRT1 paradox, we developed a circadian enzymatic model. Predictions from this model and experimental validation strongly align with the findings of Asher et al., with PER2 as the primary target of SIRT1. Further, the model suggested SIRT1 influences BMAL1 expression through actions on PGC1α. We validated this finding experimentally. Thus, our computational and experimental approaches suggest SIRT1 positively regulates clock function through actions on PER2 and PGC1α.

Keywords: SIRT1; amplitude; circadian regulation; computational model; luminescence imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Cell Line
  • Circadian Clocks / genetics*
  • Computer Simulation
  • Cytokines / genetics
  • Cytokines / metabolism
  • Feedback, Physiological*
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mice
  • Models, Biological*
  • NAD / metabolism
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Receptor Tyrosine Kinase-like Orphan Receptors / genetics
  • Receptor Tyrosine Kinase-like Orphan Receptors / metabolism
  • Signal Transduction
  • Sirtuin 1 / genetics*
  • Sirtuin 1 / metabolism

Substances

  • ARNTL Transcription Factors
  • BMAL1 protein, human
  • Cytokines
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • PER2 protein, human
  • PPARGC1A protein, human
  • Period Circadian Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • NAD
  • Luciferases
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • ROR1 protein, human
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • SIRT1 protein, human
  • Sirtuin 1