Loop extrusion promotes an alternate pathway for isotype switching

Class-switch recombination (CSR) involves replacement of the C mu constant region with another downstream C-H region. CSR is initiated by activation-induced cytidine deaminase (AID)-mediated DNA breaks that are targeted to transcriptionally active switch (S) regions. S region promoters (Prs) direct synapsis by associating with the E mu and 3'E alpha enhancers that jointly anchor a chromatin loop. We report that asymmetric loop extrusion allows 3'E alpha to track along the locus and form Pr-Pr-E interactions that mediate CSR between downstream S regions, followed by switching to donor S mu. This alternative pathway bypasses sequential switching and creates immunoglobulin (Ig)E+ B cells in the absence of IgG1 expression. Based on the analysis of diagnostic CSR products in B cell subsets, we identify a BCR-negative cell intermediate that is pivotal to efficient CSR.