Genome-wide RNA polymerase II profiles and RNA accumulation reveal kinetics of transcription and associated epigenetic changes during diurnal cycles

PLoS Biol. 2012;10(11):e1001442. doi: 10.1371/journal.pbio.1001442. Epub 2012 Nov 27.

Abstract

Interactions of cell-autonomous circadian oscillators with diurnal cycles govern the temporal compartmentalization of cell physiology in mammals. To understand the transcriptional and epigenetic basis of diurnal rhythms in mouse liver genome-wide, we generated temporal DNA occupancy profiles by RNA polymerase II (Pol II) as well as profiles of the histone modifications H3K4me3 and H3K36me3. We used these data to quantify the relationships of phases and amplitudes between different marks. We found that rhythmic Pol II recruitment at promoters rather than rhythmic transition from paused to productive elongation underlies diurnal gene transcription, a conclusion further supported by modeling. Moreover, Pol II occupancy preceded mRNA accumulation by 3 hours, consistent with mRNA half-lives. Both methylation marks showed that the epigenetic landscape is highly dynamic and globally remodeled during the 24-hour cycle. While promoters of transcribed genes had tri-methylated H3K4 even at their trough activity times, tri-methylation levels reached their peak, on average, 1 hour after Pol II. Meanwhile, rhythms in tri-methylation of H3K36 lagged transcription by 3 hours. Finally, modeling profiles of Pol II occupancy and mRNA accumulation identified three classes of genes: one showing rhythmicity both in transcriptional and mRNA accumulation, a second class with rhythmic transcription but flat mRNA levels, and a third with constant transcription but rhythmic mRNAs. The latter class emphasizes widespread temporally gated posttranscriptional regulation in the mouse liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin Assembly and Disassembly
  • Chromatin Immunoprecipitation
  • Circadian Rhythm*
  • DNA Methylation
  • Epigenesis, Genetic*
  • Half-Life
  • Histones / genetics
  • Histones / metabolism
  • Kinetics
  • Liver / cytology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Promoter Regions, Genetic
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transcription Initiation Site
  • Transcription, Genetic*
  • Transcriptome

Substances

  • Histones
  • RNA, Messenger
  • RNA Polymerase II

Grants and funding

This work was financed by CycliX, a grant from the Swiss SystemsX.ch (www.systemsx.ch) initiative evaluated by the Swiss National Science Foundation, Sybit, the SystemsX.ch IT unit, the University of Lausanne, the University of Geneva, the Ecole Polytechnique Fédérale de Lausanne (EPFL), and Vital-IT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.