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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 s...

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Detalles Bibliográficos
Autores principales: Shen, Hong Ming, Wuerffel, Robert, Cantillo, Jose F., Priyadarshi, Saurabh, Lei, Xue, Liang, Jie, Wu, Yee Ling, Kenter, Amy L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979556/
https://www.ncbi.nlm.nih.gov/pubmed/34818547
http://dx.doi.org/10.1016/j.celrep.2021.110059
Descripción
Sumario: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.