TY - JOUR
T1 - MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination
AU - Wigton, Eric J.
AU - Mikami, Yohei
AU - McMonigle, Ryan J.
AU - Castellanos, Carlos A.
AU - Wade-Vallance, Adam K.
AU - Zhou, Simon K.
AU - Kageyama, Robin
AU - Litterman, Adam
AU - Roy, Suparna
AU - Kitamura, Daisuke
AU - Dykhuizen, Emily C.
AU - Allen, Christopher D.C.
AU - Hu, Hui
AU - O’Shea, John J.
AU - Ansel, K. Mark
N1 - Funding Information:
This work was supported by funding from the National Institutes of Health (T32AI007334 to E.J. Wigton, HL109102 and HL107202 to K.M. Ansel, T32GM008361 and T32AR069516 to R.J. McMonigle), the Canadian Institutes of Health Research (Doctoral Foreign Study Award 170769 to A.K. Wade-Vallance), and flow cytometry core grants from the National Institutes of Health (P30 DK063720 to the University of California, San Francisco; P30 AR048311 to the University of Alabama at Birmingham; and P30 AI27667 to the University of Alabama at Birmingham).
Publisher Copyright:
© 2021 Wigton et al.
PY - 2021/9/29
Y1 - 2021/9/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85116563438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116563438&partnerID=8YFLogxK
U2 - 10.1084/jem.20201422
DO - 10.1084/jem.20201422
M3 - Article
C2 - 34586363
AN - SCOPUS:85116563438
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20201422
ER -