The role of miR-204 in early B cell development. (HEM1P.219)

Abstract

Abstract The generation of B lineage lymphocytes in bone marrow is contingent upon the combinatorial activities of transcription factors, signaling molecules, chromatin modifiers, and microRNAs. One transcription factor important for the generation of B cell precursors is the homeodomain protein HoxA9. Equally important as HoxA9 function in facilitating lymphoid lineage specification is silencing HoxA9 activity upon commitment to the B cell fate as sustained expression impairs later stage B cell differentiation. We previously showed that transcripts for the B cell specification factor EBF1 show an inverse expression pattern to HoxA9. Furthermore, EBF1 does not directly suppress HoxA9 transcription. Hox proteins are regulated by microRNAs in some developmental contexts. MicroRNA profiling of an EBF1-/- cell line stably expressing an inducible EBF1:ER fusion protein revealed a single miR induced by EBF1 activity, miR-204. Importantly, forced expression of miR-204 in EBF1-/- cells repressed transcription and protein levels of the HoxA9 co-factor, Meis1. We hypothesized that if Meis1 is a critical target of miR-204, then sustained expression of miR-204 should phenocopy conditional deletion of Meis1 or HoxA9. Indeed, we determined that forced expression of miR-204 in wildtype multipotent progenitors impaired B cell differentiation, similar to loss of HoxA9. These data suggest a novel role for EBF1 in B cell development, induction of miR-204 to silence a HoxA9-Meis1 transcriptional axis.