Loop extrusion promotes an alternate pathway for isotype switching.

Class-switch recombination (CSR) involves replacement of the Cμ 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 Eμ and 3′Eα enhancers that jointly anchor a chromatin loop. We report that asymmetric loop extrusion allows 3′Eα to track along the locus and form Pr-Pr-E interactions that mediate CSR between downstream S regions, followed by switching to donor Sμ. 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. [Display omitted] • Loop extrusion drives germline transcript promoter-enhancer contacts during CSR • Promoter-promoter-3′ enhancer contacts mediate reverse sequential switching • Use of the three CSR pathways is mouse strain- and Ig isotype-specific • During CSR B cells become surface BCR^neg then re-express IgM or a switched isotype Shen et al. report that 3′Eα tracks along the Igh locus via unidirectional loop extrusion to form germline transcript promoter (Pr)-Pr-E interactions that mediate an alternative CSR pathway. B cell intermediates of CSR are identified, which are AID-dependent, surface BCR-negative, and in the G 1 phase of the cell cycle. [ABSTRACT FROM AUTHOR]