MicroRNA 125b inhibition of B cell differentiation in germinal centers

• Authors: Murali Gururajan, Emory University; Christopher L. Haga, Emory University; Sabyasachi Das, Emory University; Chuen-Miin Leu, National Yang-Ming University; Daniel Hodson, The Babraham Institute; Sajni Josson, Cedars-Sinai Medical Center; Martin Turner, The Babraham Institute; Max D. Cooper, Emory University
• Journal Title: International Immunology
• Volume: Volume 22, Number 7
• Publisher: Oxford University Press | 2010-07, Pages 583-592
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1093/intimm/dxq042
• Subjects: Health Sciences, Immunology; Health Sciences, Pathology
• Keywords: BLIMP-1; centroblasts; gene regulation; IRF-4; MicroRNA; plasma cell differentiation

Abstract

MicroRNAs 125a and 125b are predicted to be able to bind to the B lymphocyte-induced maturation protein-1 (BLIMP-1) and IFN regulatory protein-4 (IRF-4) transcription factors, which are essential for plasma cell differentiation. A computational survey of the human and mouse genomes revealed that miR-125a and miR-125b are members of a multigene family located in paralogous clusters. The miR-125a cluster on chromosome 19 in humans includes miR-99b and let-7e, whereas the miR-125b cluster on chromosome 21 includes miR-99a and miR-let-7c. Our analysis of the expression profiles for these six miRs during B lineage differentiation indicated that mature miR-125a, miR-125b, miR-99b and let-7e transcripts are preferentially expressed by the actively dividing centroblasts in germinal centers (GC). However, miR-99b and let-7e are not predicted to bind BLIMP-1 or IRF-4 transcripts, and binding to the untranslated region of BLIMP-1 and IRF-4 messenger RNAs could be confirmed only for miR-125b. When the effect of miR-125b over-expression on terminal B cell differentiation was evaluated in an LPS-responsive B cell line, the induction of BLIMP-1 expression and IgM secretion was inhibited in this model system. Furthermore, miR-125b over-expression inhibited the differentiation of primary B cells and compromised the survival of cultured myeloma cells. These findings suggest that miR-125b promotes B lymphocyte diversification in GC by inhibiting premature utilization of essential transcription factors for plasma cell differentiation.