Cohesin mediates transcriptional insulation by CCCTC-binding factor

Chromosome segregation in mitosis and meiosis depends on sister chromatid cohesion mediated by cohesin complexes. Mutation of cohesin and other cohesion proteins causes transcriptional and developmental defects in animals and humans, but the molecular cause of these phenotypes is unknown. Here we describe 8811 cohesin binding sites in the human genome and show that the CCCTC-binding factor (CTCF) is associated with 88% of these. CTCF is dispensable for loading of cohesin onto DNA but is required for enrichment of cohesin at its binding sites. We provide evidence that cohesin is required for the role of CTCF sites in insulating promoters from distant enhancers. Like CTCF, cohesin is located on the maternal but not on the paternal allele of the H19 imprinting control region (ICR) and is required for imprinting of the H19-Igf2 locus. We find that cohesin is widely expressed in mammalian tissues, consistent with a cohesionindependent role in regulating gene expression. We propose that cohesin functions as a transcriptional insulator and speculate that subtle deficiencies in this function may be the cause of "cohesinopathies" such as Cornelia de Lange and Roberts syndrome. Keywords: ChIP-chip analysis