Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus

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Abstract
As well as its role in sister chromatid cohesion, the cohesin protein complex is thought be involved in the control of gene expression. Hadjur et al. show here that cohesin is involved topologically and mechanistically in long-range interactions at the cytokine locus IFNG. As well as its role in sister chromatid cohesion, cohesin is thought to have a role in the control of gene expression. Here, cohesin is shown to form the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions at the developmentally regulated cytokine locus IFNG. Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and post-replicative DNA repair1,2. In addition, evidence from model organisms3,4,5,6 and from human genetics7 suggests that cohesin is involved in the control of gene expression8,9. This non-canonical role has recently been rationalized by the findings that mammalian cohesin complexes are recruited to a subset of DNase I hypersensitive sites and to conserved noncoding sequences by the DNA-binding protein CTCF10,11,12,13. CTCF functions at insulators (which control interactions between enhancers and promoters) and at boundary elements (which demarcate regions of distinct chromatin structure)14, and cohesin contributes to its enhancer-blocking activity10,11. The underlying mechanisms remain unknown, and the full spectrum of cohesin functions remains to be determined. Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG. Hence, the ability of cohesin to constrain chromosome topology is used not only for the purpose of sister chromatid cohesion1,2, but also to dynamically define the spatial conformation of specific loci. This new aspect of cohesin function is probably important for normal development3,4,5,6 and disease7.