MicroRNA 125b inhibition of B cell differentiation in germinal centers.
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.
Gururajan
Murali
M
Department of Pathology and Laboratory Medicine, Emory University, 1462 Clifton Road NE, DSB 403, Atlanta, GA 30322, USA.
Haga
Christopher L
CL
Das
Sabyasachi
S
Leu
Chuen-Miin
CM
Hodson
Daniel
D
Josson
Sajni
S
Turner
Martin
M
Cooper
Max D
MD
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D016000:Cluster Analysis; D017124:Conserved Sequence; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D023421:Models, Animal; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D035683:MicroRNAs; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins; D000099218:Interferon Regulatory Factor-4; C531888:MIRN125 microRNA, human; C087042:PRDM1 protein, human