miRNAs are critical for the regulation of RAG expression and secondary Ig rearrangement in peripheral B lymphocytes

Autor: Sergei B Koralov, Maryaline Coffre, David Benhamou, Lili Blumenberg, David Riess, Valentina Snetkova, Marcus Hines, Tirtha Chakraborty, Kari Jensen, Marc Chong, Robert Blelloch, Dan R Littman, Doron Melamed, Jane A Skok, Klaus Rajewsky
Rok vydání: 2016
Předmět:
Zdroj: The Journal of Immunology. 196:204.33-204.33
ISSN: 1550-6606
0022-1767
Popis: The differential expression of miRNAs throughout B cell development suggests that these ncRNAs contribute to stage-specific regulation of the intricate transcriptional program during B cell development. Conditional ablation of Dicer or deletion of the miR-17~92 cluster in early pro-B cells, revealed a critical role of miRNAs in B cell differentiation. In the present study we compare the phenotypes of mice in which enzymes critical for miRNA biogenesis, Dicer, Drosha and DGCR8 are conditionally ablated in B lymphocytes, allowing us to definitively explore the role of miRNAs in B cell development and function. Global ablation of miRNAs in B lymphocytes lead to an early block in B cell development. Rescue of B cell surviva by overexpression of the anti-apopotic factor Bcl2 revealed that in the absence of miRNAs, B cells in the periphery expressed low levels of Ig heavy chain without expressing light chain. We demonstrate that miRNA-deficient B cells fail to regulate recombination machinery in the periphery, resulting in ongoing Ig light chain gene rearrangement. In addition to the upregulation of RAG1/2 in peripheral B cells, we demonstrated ongoing DNA double strand breaks at Ig light chain loci and upregulation of surrogate light chain components. We show that these events occur downstream of deregulated PI3K signaling and we recapitulate many of these defects in wild-type B lymphocytes by targeting individual components of PI3K signaling network. Furthermore, we achieve complete rescue of miRNA deficient B cells when we introduce a pro-survival Bcl2 transgene along with an Ig transgene resistant to light chain editing. Our data highlight an important and novel role for miRNAs in the maintenance of a mature phenotype in peripheral B cells.
Databáze: OpenAIRE
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