MicroRNA miR-29c regulates RAG1 expression and modulates V(D)J recombination during B cell development
Rupa Kumari, Urbi Roy, Sagar Desai, Namrata M. Nilavar, Annemarie van Nieuwenhuijze, Amita M. Paranjape, Gudapureddy Radha, Pushpinder Bawa, Mrinal Srivastava, Mridula Nambiar, Kithiganahalli Narayanaswamy Balaji, Adrian Liston, Bibha Choudhary, Sathees C. Raghavan
Abstract
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.