Transcriptional regulatory logic of the diurnal cycle in the mouse liver

PLoS Biol. 2017 Apr 17;15(4):e2001069. doi: 10.1371/journal.pbio.2001069. eCollection 2017 Apr.

Abstract

Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in the mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial fraction of all DHSs, suggesting that DHSs harbor regulatory elements that control rhythmic transcription. Using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), we found that hypersensitivity cycled in phase with RNA polymerase II (Pol II) loading and H3K27ac histone marks. We then combined the DHSs with temporal Pol II profiles in wild-type (WT) and Bmal1-/- livers to computationally identify transcription factors through which the core clock and feeding-fasting cycles control diurnal rhythms in transcription. While a similar number of mRNAs accumulated rhythmically in Bmal1-/- compared to WT livers, the amplitudes in Bmal1-/- were generally lower. The residual rhythms in Bmal1-/- reflected transcriptional regulators mediating feeding-fasting responses as well as responses to rhythmic systemic signals. Finally, the analysis of DNase I cuts at nucleotide resolution showed dynamically changing footprints consistent with dynamic binding of CLOCK:BMAL1 complexes. Structural modeling suggested that these footprints are driven by a transient heterotetramer binding configuration at peak activity. Together, our temporal DNase I mappings allowed us to decipher the global regulation of diurnal transcription rhythms in the mouse liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Chromatin Immunoprecipitation
  • Circadian Clocks / genetics
  • Circadian Rhythm / genetics*
  • Deoxyribonuclease I / genetics
  • Deoxyribonuclease I / metabolism
  • Fasting
  • Gene Expression Regulation*
  • Liver / physiology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Promoter Regions, Genetic
  • RNA Polymerase II / genetics
  • Transcription Factors / genetics
  • Transcription, Genetic

Substances

  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • Multiprotein Complexes
  • Transcription Factors
  • CLOCK Proteins
  • Clock protein, mouse
  • RNA Polymerase II
  • Deoxyribonuclease I