Loop extrusion promotes an alternate pathway for isotype switching
CELL REPORTS(2021)
Abstract
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.
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Key words
AID targeting,B cells,BCR-negative B cells,DNA breaks,IgE,chromatin looping,immunoglobulin class switch recombination,loop extrusion,sequential switching
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