MicroRNA miR-29c regulates RAG1 expression and modulates V(D)J recombination during B cell development

Recombination activating genes (RAGs), consisting of RAG1 and RAG2, are stringently regulated lymphoid-specific genes, which initiate V(D)J recombination in developing lymphocytes. We report the regulation of RAG1 through a microRNA (miRNA), miR-29c, in a B cell stage-specific manner in mice and humans. Various lines of experimentation, including CRISPR-Cas9 genome editing, demonstrate the target specificity and direct interaction of miR-29c to RAG1. Modulation of miR-29c levels leads to change in V(D)J recombination efficiency in pre-B cells. The miR-29c expression is inversely proportional to RAG1 in a B cell developmental stage-specific manner, and miR-29c null mice exhibit a reduction in mature B cells. A negative correlation of miR-29c and RAG1 levels is also observed in leukemia patients, suggesting the potential use of miR-29c as a biomarker and a therapeutic target. Thus, our results reveal the role of miRNA in the regulation of RAG1 and its relevance in cancer. [Display omitted] •miR-29c regulates RAG1 expression in mice and humans•miR-29c modulates V(D)J recombination in pre-B cells by regulating RAG1 expression•miR-29c and Rag1 expression are inversely correlated in developing B cells in mice•Leukemia patients show a negative correlation for expression of miR-29c and RAG1 Kumari et al. report that miR-29c is a negative regulator of RAG1 in B cells of mice and humans. Overexpression of miR-29c reduces V(D)J recombination, while its quenching increases the efficiency of recombination. miR-29c holds potential as a biomarker and in cancer therapeutics.