Genome-Wide Control of RNA Polymerase II Activity by Cohesin

Abstract

Cohesin is a well-known mediator of sister chromatid cohesion, but it also influences gene expression and development. These non-canonical roles of cohesin are not well understood, but are vital: gene expression and development are altered by modest changes in cohesin function that do not disrupt chromatid cohesion. To clarify cohesin's roles in transcription, we measured how cohesin controls RNA polymerase II (Pol II) activity by genome-wide chromatin immunoprecipitation and precision global run-on sequencing. On average, cohesin-binding genes have more transcriptionally active Pol II and promoter-proximal Pol II pausing than non-binding genes, and are more efficient, producing higher steady state levels of mRNA per transcribing Pol II complex. Cohesin depletion frequently decreases gene body transcription but increases pausing at cohesin-binding genes, indicating that cohesin often facilitates transition of paused Pol II to elongation. In many cases, this likely reflects a role for cohesin in transcriptional enhancer function. Strikingly, more than 95% of predicted extragenic enhancers bind cohesin, and cohesin depletion can reduce their association with Pol II, indicating that cohesin facilitates enhancer-promoter contact. Cohesin depletion decreases the levels of transcriptionally engaged Pol II at the promoters of most genes that don't bind cohesin, suggesting that cohesin controls expression of one or more broadly acting general transcription factors. The multiple transcriptional roles of cohesin revealed by these studies likely underlie the growth and developmental deficits caused by minor changes in cohesin activity.

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

“…In addition, genome-wide studies suggest the association between cohesin and RNA polymerase II (Pol II), which is also the interacting partner of the TFIID complex (ref. 17 and Figure 7). TFIID is a megadalton-sized multiprotein complex necessary for RNA Pol II-initiated transcription, which reads epigenetic markers or interacts with transcriptional activators.…”

“…Evidence suggests that NIPBL, SMC1A, SMC3, RAD21, and HDAC8, the 5 genes associated with cohesin and CdLS, are each involved in transcriptional regulation (11)(12)(13)(14)(15)(16)(17). Variant alleles in genes encoding proteins important to cohesion function are also associated with other syndromes sharing phenotypic features with CdLS, such as Roberts-SC phocomelia syndrome (MIM # 268300, MIM # 269000) (18) and Warsaw breakage syndrome (MIM # 613398) (19).…”

Cohesin in development and disease

“…More recently, it was shown that cohesin can counteract silencing by Polycomb proteins, although in some cases it can cooperate with Polycomb to restrain transcription (Cunningham et al, 2012; Hallson et al, 2008;Schaaf et al, 2009). Finally, cohesin appears to both positively and negatively affect the transition from paused RNA polymerase to transcription elongation (Fay et al, 2011;Schaaf et al, 2013).…”

“…More recently, it was shown that cohesin can counteract silencing by Polycomb proteins, although in some cases it can cooperate with Polycomb to restrain transcription (Cunningham et al, 2012; Hallson et al, 2008;Schaaf et al, 2009). Finally, cohesin appears to both positively and negatively affect the transition from paused RNA polymerase to transcription elongation (Fay et al, 2011;Schaaf et al, 2013).In mammals, cohesin colocalizes with the transcriptional insulator CTCF (CCCTC-binding factor) and mediates transcriptional insulation (Parelho et al, 2008;Wendt et al, 2008). Cohesin performs this function by promoting the formation of chromatin loops in collaboration with CTCF at several loci, including the developmentally regulated interferon γ (Ifng) locus (Hadjur et al, 2009), the apolipoprotein gene cluster (Mishiro et al, 2009), the Igf2/H19 locus (Nativio et al, 2009) and the β-globin locus and the surrounding olfactory receptor genes (Chien et al, 2011; Hou et al, 2010).…”

The torments of the cohesin ring

“…10,24 In the in vitro assays, the presumably partially collapsed rings were pushed by the T7 RNA polymerase and the FtsK motor protein. A collapsed ring on the DNA is likely to present an obstacle to transcription, replication, and repair in vivo and might contribute to the reported roles of cohesin in regulating transcriptional elongation 37,38 and blocking DNA synthesis in the presence of radiation-induced damage.…”