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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 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.

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Figure 1: Developmentally regulated cohesin and CTCF binding at IFNG.
Figure 2: Cell-type-specific long-range chromosomal interactions at IFNG are based on CTCF/cohesin sites.
Figure 3: Long-range chromosomal interactions at IFNG require cohesin.

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Acknowledgements

We thank M. Messi, F. Sallusto and L. Bruno for help and advice with human T cells, L. Aragon for discussions, M. Leleu and M. Spivakov for help with informatics, D. Dormann for help with image analysis and E. Ng, E. O’Connor and P. Hexley for cell sorting. Supported by the Medical Research Council, UK.

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Correspondence to Matthias Merkenschlager.

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Hadjur, S., Williams, L., Ryan, N. et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460, 410–413 (2009). https://doi.org/10.1038/nature08079

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