MIR-23A microRNA cluster inhibits B-cell development

Abstract

Objective The transcription factor PU.1 (encoded by Sfpi1) promotes myeloid differentiation but it is unclear what downstream genes are involved. MiRNAs are a class of small RNAs that regulate many cellular pathways including proliferation, survival and differentiation. The objective of this study was to identify miRNAs downstream of PU.1 that regulate hematopoietic development. Materials and Methods MiRNAs that change expression in a PU.1-inducible cell line were identified with microarrays. The promoter for a miRNA cluster upregulated by PU.1 induction was analyzed for PU.1 binding by electrophoretic mobility shift and chromatin immunoprecipitation assays. Retroviral transduction of hematopoietic progenitors was performed to evaluate the effect of miRNA expression on hematopoietic development in vitro and in vivo. Results We identified a miRNA cluster whose pri-transcript is regulated by PU.1. The pri-miRNA encodes three mature miRNAs: miR-23a, miR-27a, and miR-24-2. Each miRNA is more abundant in myeloid cells compared to lymphoid cells. When hematopoietic progenitors expressing the 23a cluster miRNAs were cultured in B cell promoting conditions we observed a dramatic decrease in B lymphopoiesis and an increase in myelopoiesis compared to control cultures. In vivo, hematopoietic progenitors expressing the miR-23a cluster generate reduced numbers of B cells compared to control cells. Conclusions The miR-23a cluster is a downstream target of PU.1 involved in antagonizing lymphoid cell fate acquisition. Although miRNAs have been identified downstream of PU.1 in mediating the development of monocytes and granulocytes, the 23a cluster is the first downstream miRNA target implicated in regulating the development of myeloid versus lymphoid cells.

MicroRNA‑23a/24‑2/27a as a potential diagnostic biomarker for cancer: A systematic review and meta‑analysis

“…Huang et al demonstrated that a high expression level of miR-23a/24/27a decreased transforming growth factor-β-induced tumor-suppressive activity in a Smad-dependent manner in HCC (9) and lung cancer (36). Furthermore, the cluster was also found to be involved in altering lymphoid cell differentiation via the transcription factor PU.1 (37). An increasing number of studies demonstrated that several miRNA clusters may regulate the occurrence and development of cancer by cooperating with the c-Myc oncogene (38)(39)(40).…”

MicroRNAs as novel regulators of stem cell fate

“…During the adipogenic differentiation of mouse ESCs, the expression of miR-10b, miR-15, miR26a, miR-30a-5p, miR-30c, miR-98, miR-99a, miR-103, miR-143, miR-148a, miR-152, miR-224, miR-422b, and miR-let-7b increased, whereas the expression of the miR-17-92 cluster was downregulated [143] . Myeloid differentiation is promoted by PU.1 transcription factor, and the overexpression of the miR-23a cluster in hematopoietic progenitor cells suppresses B-cell development [144] . Furthermore, miRNAs are involved in the differentiation of diploid spermatogonia to haploid spermatozoa.…”

Macrophage development from HSCs requires PU.1-coordinated microRNA expression

“…by guest www.bloodjournal.org From to delineate PU.1-dependent miRs showed a limited number of miR candidates, of which the miR-23 cluster was shown to block lymphopoiesis; however, that study did not clarify a specific myeloid profile. 42 Therefore, our analysis of PU.1-dependent miRs reveals PU.1 as a master coordinator of myeloid miR expression.…”

“…Because other studies failed to detect a lineage specification effect of miR-146a during adult hematopoiesis in vitro, 38,42 we chose to analyze its function in vivo using a BM transplantation approach. Recently, Starczynowski et al 17 found a transient increase in peripheral blood myeloid cell numbers after transplanting miR146a-overexpressing, 5-fluoruracil-treated donor BM cells, which diminished over time.…”