Regulation of circadian clock transcriptional output by CLOCK:BMAL1

PLoS Genet. 2018 Jan 4;14(1):e1007156. doi: 10.1371/journal.pgen.1007156. eCollection 2018 Jan.


The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of 15% of the transcriptome and control the daily regulation of biological functions. The recent characterization of CLOCK:BMAL1 cistrome revealed that although CLOCK:BMAL1 binds synchronously to all of its target genes, its transcriptional output is highly heterogeneous. By performing a meta-analysis of several independent genome-wide datasets, we found that the binding of other transcription factors at CLOCK:BMAL1 enhancers likely contribute to the heterogeneity of CLOCK:BMAL1 transcriptional output. While CLOCK:BMAL1 rhythmic DNA binding promotes rhythmic nucleosome removal, it is not sufficient to generate transcriptionally active enhancers as assessed by H3K27ac signal, RNA Polymerase II recruitment, and eRNA expression. Instead, the transcriptional activity of CLOCK:BMAL1 enhancers appears to rely on the activity of ubiquitously expressed transcription factors, and not tissue-specific transcription factors, recruited at nearby binding sites. The contribution of other transcription factors is exemplified by how fasting, which effects several transcription factors but not CLOCK:BMAL1, either decreases or increases the amplitude of many rhythmically expressed CLOCK:BMAL1 target genes. Together, our analysis suggests that CLOCK:BMAL1 promotes a transcriptionally permissive chromatin landscape that primes its target genes for transcription activation rather than directly activating transcription, and provides a new framework to explain how environmental or pathological conditions can reprogram the rhythmic expression of clock-controlled genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / metabolism
  • ARNTL Transcription Factors / physiology*
  • Animals
  • Binding Sites / genetics
  • CLOCK Proteins / metabolism
  • CLOCK Proteins / physiology*
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation*
  • Mice
  • Protein Binding
  • Transcription, Genetic*


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • CLOCK Proteins
  • Clock protein, mouse

Grants and funding

This work was supported in part by Texas A&M University start up funds (JSM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.