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.
Highlights
Non-coding RNAs, including microRNAs, play a critical role in regulating hematopoietic gene expression networks
We previously identified a gene that codes for 3 miRNAs that control the development of immune cells in the bone marrow
Since multipotential progenitors (MPPs) populations were unchanged in mirn23a-/mice, this suggested that mirn23a null MPPs are more biased towards the common lymphoid progenitors (CLPs) lineage than wildtype MPPs
Summary
Non-coding RNAs, including microRNAs (miRNAs), play a critical role in regulating hematopoietic gene expression networks. Overexpression of mirn23a in hematopoietic progenitors biases cell fate decisions towards the myeloid lineage at the expense of the lymphoid lineage both in vitro and in vivo[3]. We reported that when mirn23a is deleted from mice, there is an increase in B cell development and a concomitant decrease in myelopoiesis in the bone marrow that persists in the periphery. This differentiation bias occurs early during hematopoietic development, as an increase in common lymphoid progenitors (CLPs) is observed in mirn23a-/- bone marrow, as well as a decrease in common myeloid progenitors (CMPs), granulocyte/ monocyte progenitors (GMPs) and megakaryocyte/ erythroid progenitors (MEPs). The hematopoietic targets that mirn23a regulates to drive myeloid cell development are not clear
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