Abstract
Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and post-replicative DNA repair1,2. In addition, evidence from model organisms3-6 and from human genetics7 suggests that cohesin plays a role 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 (HSS) and to conserved non-coding sequences by the DNA binding protein CTCF10-13. 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 activity10,11. 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 cohesion1,2, but also to dynamically define the spatial conformation of specific loci. This novel aspect of cohesin function is likely of importance to normal development3-6 and to disease7.
Highlights
Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and postreplicative DNA repair[1,2]
One model of CTCF function is the formation of chromatin loops, which have been demonstrated at the H19/IGF2, beta globin and MHC class II loci[15,16,17]
Real time RT-PCR showed that IFNG transcripts were highly induced upon activation of CCR5+ Th1 cells and intracellular staining showed the inducible expression of IFNγ protein in CCR5+ Th1 cells, while CRTH2+ Th2 cells expressed interleukin-4 (IL4, figure 1c)
Summary
Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and postreplicative DNA repair[1,2]. Genomic tiling arrays[10] showed major binding sites for the cohesin subunit Rad[21] and CTCF at −73 and +66 kb in mouse lymphoid cell lines (figure 1a).
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