Cohesin regulates tissue-specific expression by stabilizing highly occupied cis-regulatory modules

Genome Res. 2012 Nov;22(11):2163-75. doi: 10.1101/gr.136507.111. Epub 2012 Jul 10.

Abstract

The cohesin protein complex contributes to transcriptional regulation in a CTCF-independent manner by colocalizing with master regulators at tissue-specific loci. The regulation of transcription involves the concerted action of multiple transcription factors (TFs) and cohesin's role in this context of combinatorial TF binding remains unexplored. To investigate cohesin-non-CTCF (CNC) binding events in vivo we mapped cohesin and CTCF, as well as a collection of tissue-specific and ubiquitous transcriptional regulators using ChIP-seq in primary mouse liver. We observe a positive correlation between the number of distinct TFs bound and the presence of CNC sites. In contrast to regions of the genome where cohesin and CTCF colocalize, CNC sites coincide with the binding of master regulators and enhancer-markers and are significantly associated with liver-specific expressed genes. We also show that cohesin presence partially explains the commonly observed discrepancy between TF motif score and ChIP signal. Evidence from these statistical analyses in wild-type cells, and comparisons to maps of TF binding in Rad21-cohesin haploinsufficient mouse liver, suggests that cohesin helps to stabilize large protein-DNA complexes. Finally, we observe that the presence of mirrored CTCF binding events at promoters and their nearby cohesin-bound enhancers is associated with elevated expression levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCCTC-Binding Factor
  • Cell Cycle Proteins / metabolism*
  • Chromatin Immunoprecipitation
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA-Binding Proteins
  • Gene Regulatory Networks*
  • Genome
  • Haploinsufficiency
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Organ Specificity
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Repressor Proteins / metabolism
  • Sequence Analysis, DNA
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Up-Regulation

Substances

  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Ctcf protein, mouse
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Rad21 protein, mouse
  • Repressor Proteins
  • Transcription Factors
  • cohesins