Open AccessMicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination
Author(s) -
Eric J. Wigton,
Yohei Mikami,
Ryan J. McMonigle,
Carlos A. Castellanos,
Adam K. Wade-Vallance,
Simon Zhou,
Robin Kageyama,
Adam J. Litterman,
Suparna Roy,
Daisuke Kitamura,
Emily C. Dykhuizen,
Christopher D.C. Allen,
Hui Hu,
John J. O’Shea,
K. Mark Ansel
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201422
Subject(s) - microrna , biology , immunoglobulin class switching , regulator , microbiology and biotechnology , regulation of gene expression , gene silencing , gene , gene expression , b cell , genetics , antibody
MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222–deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1.