The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis

Abstract

MicroRNA cluster mirn23a has previously been shown to promote myeloid development at the expense of lymphoid development in overexpression and knockout mouse models. This polarization is observed early in hematopoietic development, with an increase in common lymphoid progenitors (CLPs) and a decrease in all myeloid progenitor subsets in adult bone marrow. The pool size of multipotential progenitors (MPPs) is unchanged; however, in this report we observe by flow cytometry that polarized subsets of MPPs are changed in the absence of mirn23a. Additionally, in vitro culture of MPPs and sorted MPP transplants showed that these cells have decreased myeloid and increased lymphoid potential in vitro and in vivo. We investigated the mechanism by which mirn23a regulates hematopoietic differentiation and observed that mirn23a promotes myeloid development of hematopoietic progenitors through regulation of hematopoietic transcription factors and signaling pathways. Early transcription factors that direct the commitment of MPPs to CLPs (Ikzf1, Runx1, Satb1, Bach1 and Bach2) are increased in the absence of mirn23a miRNAs as well as factors that commit the CLP to the B cell lineage (FoxO1, Ebf1, and Pax5). Mirn23a appears to buffer transcription factor levels so that they do not stochastically reach a threshold level to direct differentiation. Intriguingly, mirn23a also inversely regulates the PI3 kinase (PI3K)/Akt and BMP/Smad signaling pathways. Pharmacological inhibitor studies, coupled with dominant active/dominant negative biochemical experiments, show that both signaling pathways are critical to mirn23a’s regulation of hematopoietic differentiation. Lastly, consistent with mirn23a being a physiological inhibitor of B cell development, we observed that the essential B cell transcription factor EBF1 represses expression of mirn23a. In summary, our data demonstrates that mirn23a regulates a complex array of transcription and signaling pathways to modulate adult hematopoiesis.

Global pathway view analysis of microRNA clusters in myasthenia gravis

“…The mirn23a gene, which encodes miR-23a, -24-2 and -27a, transforms into the mirn23a cluster and is also central to T cell differentiation (44); however, antagonizes B cell development (45) unlike the miR-17-92 cluster. The mirn23a cluster was previously reported to be involved in the pathogenesis of immune-associated diseases, including hematopoiesis (14), CKD-induced muscle atrophy (50), leukemia (51) and a number of types of carcinoma (52). These results further support the potential association between miRNA clusters and immunity, and even the mechanism of MG. Additionally, 10 miRNA clusters that have not been reported previously were identified through the global analysis of MG risk miRNA clusters in the present study.…”

“…For example, the miR-106a-363 cluster encodes six miRNAs on the X chromosome, which include miR-18b, miR-106a and miR-363-3p, that were demonstrated to be involved in T-helper 17 cell differentiation, which further illustrates the association between the miR-106-363 cluster and immune-associated diseases (12,13). The mirn23a gene is located on murine chromosome 8 and codes for three pre-miRNAs, miR-23a, miR-24-2 and miR-27a (14). The miR-23a-27a-24-2 miRNA cluster is an inhibitor of B cell development, and bone morphogenetic protein/mothers against decapentaplegic and Akt/FOXO1 signaling is critical for mirn23a-mediated immune cell regulation (14).…”

“…The present study located each MG risk miRNA on each chromosome and identified 15 significant miRNA clusters, with distances <6 kb, associated with MG. Among the 15 miRNA clusters, at least five miRNA clusters were identified that have been reported to be associated with immunity, including the miR-25-93-106b cluster (37), which comprises hsa-miR-106b-3p, hsa-miR-106b-5p, hsa-miR-93-5p and hsa-miR-25-3p on chromosome 7; the let-7 family cluster (38), comprising hsa-let-7d-5p, hsa-let-7f-5p, hsa-let-7f-1-3p and hsa-let-7a-5p on chromosome 9; the miR-17-92 cluster (39)(40)(41)(42), comprising hsa-miR-92a-3p, hsa-miR-20a-5p and hsa-miR-17-5p on chromosome 13; the miR-23a-27a-24-2 cluster (14,(43)(44)(45), comprising hsa-miR-23a-3p, hsa-miR-27a-3p and hsa-miR-24-3p on chromosome 19; and the miR-106a-363 cluster (12,13), comprising hsa-miR-92a-3p, hsa-miR-363-3p, hsa-miR-20b-5p and hsa-miR-18b-3p on the X chromosome.…”

“…The mirn23a gene is located on murine chromosome 8 and codes for three pre-miRNAs, miR-23a, miR-24-2 and miR-27a (14). The miR-23a-27a-24-2 miRNA cluster is an inhibitor of B cell development, and bone morphogenetic protein/mothers against decapentaplegic and Akt/FOXO1 signaling is critical for mirn23a-mediated immune cell regulation (14). However, there has been no overall investigation of miRNA clusters in MG.…”

MicroRNAs associated to single drug components of R-CHOP identifies diffuse large B-cell lymphoma patients with poor outcome and adds prognostic value to the international prognostic index

“…The miRNAs included in the final model are well studied miRNAs with known functions in normal B-cell differentiation and tumorigenesis [13,49,50]. miR-21 and miR-155 has been reported to be upregulated and to possess oncogenic properties in numerous cancers including breast cancer, glioblastoma, and DLBCL [51][52][53][54][55].…”