Figure 6. Polymorphisms in CTCF/Cohesin alter DSB position and frequency.

(A) Left panel, Venn diagram of CTCF⁺RAD21⁺ sites of Mus spretus (Spretus) and Mus musculus (C57BL/6) in activated B-cells. Right panel, comparison of the fraction of sites that break between shared, C57BL/6 and Spretus CTCF⁺RAD21⁺ sites (Chi-square test for independence, p<1×10⁻²⁰). (B–D) Examples of DSB sites that are shared or exclusive between Spretus and C57BL/6. DSB profiles upon ETO treatment and CTCF/RAD21 occupancy measured by ChIP-seq for each species is shown. (E) Ratio of DSB levels and RAD21 occupancy between C57BL/6 and Spretus at shared CTCF⁺RAD21⁺ binding sites are compared (Spearman correlation, ρ=0.56; p<1e-15). (F) Comparison between integrated NIPBL binding within the loops (defined by Hi-C) and DSBs located at corresponding loop anchors (Spearman correlation, ρ=0.54; p<1×10⁻¹⁵), as illustrated below. (G) Extruding cohesin rings (green) load (black arrow) and travel through the chromatin fiber until they are trapped by a pair of adjacent CTCF proteins positioned in a convergent orientation (blue and red triangles). As the extrusion complex advances, entanglements or knots build up ahead of the motor. TOP2B (purple) maybe necessary to relieve accumulated topological stress to promote loop formation. DSBs also have the potential to drive mutation and chromosomal rearrangements that promote cancer.