Cohesin at active genes: a unifying theme for cohesin and gene expression from model organisms to humans

Abstract

Cohesin is an evolutionarily ancient multisubunit protein complex with a deeply conserved function: it provides cohesion between sister chromatids from the time of DNA replication in S-phase until mitosis. This cohesion facilitates repair of damage that occurs during DNA replication, and, crucially, enforces faithful segregation of chromosomes upon cell division. Cohesin also influences gene expression, and relative to sister chromatid cohesion, gene expression is exquisitely sensitive to moderate changes in cohesin activity. Early studies revealed differences in cohesin's roles in gene expression between various organisms. In all organisms examined, however, cohesin marks a subset of active genes. This review focuses on the roles of cohesin at active genes, and to what extent these roles are conserved between organisms.

Figure 1

Cohesin and the kollerin and releasin complexes that control cohesin chromosome binding dynamics during interphase. The various organism-specific names for each protein subunit of the complexes in Drosophila, mammals and yeast are given. Cohesin topologically encircles DNA, and during interphase, is loaded onto chromosomes by kollerin, which requires ATP hydrolysis by the cohesin Smc subunits, and is removed by the releasin complex (57). Releasin interacts with the cohesin SA subunit, and Sororin (not shown; Dalmatian in Drosophila) interacts with Pds5 to counteract Wapl and the cohesin removal activity (58).

Figure 2

Cohesin and it’s proposed functions at active gene promoters in metazoan organisms. As described in the text, outside of CTCF sites in mammalian cells, kollerin and cohesin levels are highest at transcriptional enhancers and active gene promoters in which RNA polymerase (Pol II) pauses after transcribing several nucleotides. Pausing requires the NELF (negative elongation factor) and DSIF (DRB-sensitivity inducing factor), but they are not required for cohesin binding or vice versa. The Mediator complex interacts with cohesin and is present at virtually all cohesin-bound enhancers and promoters. Current evidence indicates that cohesin stabilizes DNA loops that bring the enhancer and promoter into contact, and thereby stimulate phosphorylation of Pol II, NELF, and DSIF by the P-TEFb complex (CycT, Cdk9) recruited by transcriptional activators and release the paused Pol II into active elongation.