Long-Range Chromosome Interactions Mediated by Cohesin Shape Circadian Gene Expression

PLoS Genet. 2016 May 2;12(5):e1005992. doi: 10.1371/journal.pgen.1005992. eCollection 2016 May.


Mammalian circadian rhythm is established by the negative feedback loops consisting of a set of clock genes, which lead to the circadian expression of thousands of downstream genes in vivo. As genome-wide transcription is organized under the high-order chromosome structure, it is largely uncharted how circadian gene expression is influenced by chromosome architecture. We focus on the function of chromatin structure proteins cohesin as well as CTCF (CCCTC-binding factor) in circadian rhythm. Using circular chromosome conformation capture sequencing, we systematically examined the interacting loci of a Bmal1-bound super-enhancer upstream of a clock gene Nr1d1 in mouse liver. These interactions are largely stable in the circadian cycle and cohesin binding sites are enriched in the interactome. Global analysis showed that cohesin-CTCF co-binding sites tend to insulate the phases of circadian oscillating genes while cohesin-non-CTCF sites are associated with high circadian rhythmicity of transcription. A model integrating the effects of cohesin and CTCF markedly improved the mechanistic understanding of circadian gene expression. Further experiments in cohesin knockout cells demonstrated that cohesin is required at least in part for driving the circadian gene expression by facilitating the enhancer-promoter looping. This study provided a novel insight into the relationship between circadian transcriptome and the high-order chromosome structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics*
  • ARNTL Transcription Factors / metabolism
  • Animals
  • CCCTC-Binding Factor
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosomes / genetics
  • Circadian Rhythm / genetics*
  • Feedback, Physiological
  • GA-Binding Protein Transcription Factor / genetics
  • GA-Binding Protein Transcription Factor / metabolism
  • Gene Expression Regulation
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics*
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Ctcf protein, mouse
  • GA-Binding Protein Transcription Factor
  • Gabpa protein, mouse
  • Nr1d1 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • RAD21L protein, mouse
  • Repressor Proteins
  • Stag2 protein, mouse
  • cohesins

Grant support

This work was supported by Chinese Academy of Sciences Strategic Priority Research Program Grant XDB02060006 (JY) and Natural Science Foundation of China Grant 31571209 (JY), National Basic Research Program of China grant 2013CB966802 (ZZ), and National Natural Science Foundation of China grant 31370762 (ZZ). JY is an Independent Research Group leader supported by both Chinese Academy of Sciences and German Max-Planck Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.