BLIMP-1 and STAT3 counterregulate microRNA-21 during plasma cell differentiation.
During cellular differentiation, mRNA transcription and translation require precise coordination. The mechanisms controlling this are not well defined. IL-21 is an important regulator of plasma cell differentiation, and it controls the master regulator of plasma cell differentiation, B lymphocyte-induced maturation protein-1 (BLIMP-1), via STAT3 and IRF4. Among the other targets of STAT3 is microRNA-21 (miR-21). miR-21 is the most frequently deregulated microRNA in malignancy, including B cell lymphomas, and it has oncogenic potential downstream of STAT3. However, the regulation and function of miR-21 during plasma cell differentiation are not characterized. In contrast to the induction of miR-21 observed in response to STAT3 activation in other systems, we demonstrate that miR-21 is repressed during IL-21-driven plasma cell differentiation. We explored the molecular basis for this repression and identify primary miR-21 transcription as a direct target of BLIMP-1-dependent repression, despite continued STAT3 activation and phospho-STAT3 binding to the primary miR-21 promoter. Thus, STAT3 and BLIMP-1 constitute an incoherent feed-forward loop downstream of IL-21 that can coordinate microRNA with mRNA expression during plasma cell differentiation.
Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, United Kingdom.
Nicholas A
NA
Barnes
Sophie
S
Stephenson
Mario
M
Cocco
Reuben M
RM
Tooze
Gina M
GM
Doody
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology; D025461:Feedback, Physiological / Q000502:physiology*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007739:L Cells; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1