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

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 tissuespecific 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 wildtype 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.

Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments

“…In addition, cohesin contributes to the regulation of gene expression by mechanisms thought to involve long-range interactions between its binding sites at regulatory elements associated with CTCF (Parelho et al 2008;Rubio et al 2008;Stedman et al 2008;Wendt et al 2008) or with active promoters and enhancers (Misulovin et al 2008;Kagey et al 2010;Schmidt et al 2010;Faure et al 2012;Dorsett and Merkenschlager 2013). Taken together these properties suggest a role for cohesin in genome organization.…”

“…Raw read alignment, filtering, and peak-calling for RAD21, MED1, NIPBL CTCF, and definition of CNCs was done as previously described (Faure et al 2012). ChIP-seq data for H3K27me3 (Zhang et al 2012) was similarly processed, except CCAT version 3.0 (Xu et al 2010) was used to identify the relatively broad regions occupied by this mark (precompiled histone modification configuration).…”

Genome-wide and parental allele-specific analysis of CTCF and cohesin DNA binding in mouse brain reveals a tissue-specific binding pattern and an association with imprinted differentially methylated regions

“…This supports the idea that different functions may be a result of the context of CTCF binding (Gaszner and Felsenfeld 2006), and it is possible that coordinate binding of cohesin may influence CTCF. Cohesin is involved in tissue-specific transcriptional control (Faure et al 2012) and associated with the Mediator complex, which has a role in transcriptional activation (Taatjes 2012). Studies have shown a link between cohesin, the Mediator complex, transcription, and chromatin looping (Kagey et al 2010).…”

Chromatin features and the epigenetic regulation of pluripotency states in ESCs

“…Depletion of cohesin results in reduced DNA accessibility and transcription factor binding, indicating a causative role for cohesin in promoting the formation of these transcription factor clusters . Cohesin may thus help to confer robustness in gene expression by helping to stabilize highly occupied cis-regulatory modules (Faure et al, 2012) (Fig. 1).…”