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

Abstract

Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and post-replicative DNA repair 1, 2. In addition, evidence from model organisms 3- 6 and from human genetics 7 suggests that cohesin plays a role in the control of gene expression 8, 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 (HSS) and to conserved non-coding sequences by the DNA binding protein CTCF 10- 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 CTCF’s enhancer blocking activity 10, 11. The underlying mechanisms remain unknown, and the full spectrum of cohesin functions remains to be elucidated. 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, cohesin’s ability to constrain chromosome topology is utilized not only for the purpose of sister chromatid cohesion 1, 2, but also to dynamically define the spatial conformation of specific loci. This novel aspect of cohesin function is likely of importance to normal development 3- 6 and to disease 7.