Journal
INTERNATIONAL IMMUNOLOGY
Volume 22, Issue 7, Pages 583-592Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxq042
Keywords
BLIMP-1; centroblasts; gene regulation; IRF-4; MicroRNA; plasma cell differentiation
Categories
Funding
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI39816]
- Biotechnology and Biological Sciences Research Council
- Medical Research Council, UK
- Cancer Research UK
- Emory University School of Medicine
- Georgia Research Alliance
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000H190] Funding Source: researchfish
- Medical Research Council [G0601618] Funding Source: researchfish
- BBSRC [BBS/E/B/0000H190] Funding Source: UKRI
- MRC [G0601618] Funding Source: UKRI
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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.
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