Cohesin regulates tissue-specific expression by stabilising highly occupied cis-regulatory modules
- Andre J Faure1,
- Dominic Schmidt2,
- Stephen Watt2,
- Petra C Schwalie1,
- Michael D Wilson2,
- Huiling Xu3,
- Robert G Ramsay3,
- Duncan T Odom2 and
- Paul Flicek1,4
- 1 European Bioinformatics Institute;
- 2 Cancer Research UK, Cambridge Research Institute;
- 3 University of Melbourne, Parkville, Victoria, Australia
- ↵* Corresponding author; email: flicek{at}ebi.ac.uk
Abstract
The cohesin protein complex contributes to transcriptional regulation in a CTCF-independent manner by colocalising 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 colocalise, 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 stabilise 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.
- Received December 16, 2011.
- Accepted July 9, 2012.
- © 2012, Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
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