MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation

Nat Commun. 2016 Jun 24;7:11807. doi: 10.1038/ncomms11807.

Abstract

The circadian clock and the cell cycle are major cellular systems that organize global physiology in temporal fashion. It seems conceivable that the potentially conflicting programs are coordinated. We show here that overexpression of MYC in U2OS cells attenuates the clock and conversely promotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation. Inhibition of the circadian clock is crucially dependent on the formation of repressive complexes of MYC with MIZ1 and subsequent downregulation of the core clock genes BMAL1 (ARNTL), CLOCK and NPAS2. We show furthermore that BMAL1 expression levels correlate inversely with MYC levels in 102 human lymphomas. Our data suggest that MYC acts as a master coordinator that inversely modulates the impact of cell cycle and circadian clock on gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / physiology*
  • Cell Line
  • Cell Proliferation / physiology*
  • Circadian Clocks / physiology*
  • Gene Expression Regulation / physiology*
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Lymphoma / metabolism
  • Osteosarcoma / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*

Substances

  • Kruppel-Like Transcription Factors
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • ZBTB17 protein, human