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.
Highlights
Cohesin is a large protein ring that topologically encircles DNA and participates in several chromosome functions, including sister chromatid cohesion, chromosome segregation, DNA repair, and gene expression
We used genome-wide chromatin immunoprecipitation with tiling microarrays (ChIP-chip) to measure the genome-wide binding of polymerase II (Pol II), the Cyclin T (CycT) subunit of the P-TEFb complex, and the Cdk12 Pol II kinase in ML-DmBG3 (BG3) Drosophila cells derived from larval central nervous system
Pol II positively correlates with the CycT subunit of the P-TEFb Pol II kinase (0.64–0.67), and somewhat less, significantly, with the Cdk12 kinase (0.39–0.45) (Table 1)
Summary
Cohesin is a large protein ring that topologically encircles DNA and participates in several chromosome functions, including sister chromatid cohesion, chromosome segregation, DNA repair, and gene expression (reviewed in [1,2,3]). It is loaded onto chromosomes by the kollerin complex, and removed by the releasin complex. Kollerin or releasin activity alter gene expression, growth, and animal development without measurable defects in chromatid cohesion or chromosome segregation. Cohesin’s role in gene expression appears largely independent of its role in cell division, and considerably more sensitive than its other cellular functions to changes in cohesin dosage
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