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

Jeffrey L. Kurkewich, Justin Hansen, Nathan Klopfenstein, Helen Zhang, Christian Wood, Austin Boucher, Joseph Hickman, David E. Muench, H. Leighton Grimes, Richard Dahl

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1006887
JournalPLoS Genetics
Volume13
Issue number7
DOIs
StatePublished - Jul 1 2017

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hematopoiesis
Lymphoid Progenitor Cells
Hematopoiesis
MicroRNAs
microRNA
Buffers
Transcription Factors
buffers
transcription factors
transcription (genetics)
B-lymphocytes
inhibitor
B-Lymphocytes
Critical Pathways
B-Lymphoid Precursor Cells
flow cytometry
Cell Lineage
Phosphatidylinositol 3-Kinases
Knockout Mice
in vitro culture

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis. / Kurkewich, Jeffrey L.; Hansen, Justin; Klopfenstein, Nathan; Zhang, Helen; Wood, Christian; Boucher, Austin; Hickman, Joseph; Muench, David E.; Grimes, H. Leighton; Dahl, Richard.

In: PLoS Genetics, Vol. 13, No. 7, e1006887, 01.07.2017.

Research output: Contribution to journalArticle

Kurkewich, JL, Hansen, J, Klopfenstein, N, Zhang, H, Wood, C, Boucher, A, Hickman, J, Muench, DE, Grimes, HL & Dahl, R 2017, 'The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis', PLoS Genetics, vol. 13, no. 7, e1006887. https://doi.org/10.1371/journal.pgen.1006887
Kurkewich, Jeffrey L. ; Hansen, Justin ; Klopfenstein, Nathan ; Zhang, Helen ; Wood, Christian ; Boucher, Austin ; Hickman, Joseph ; Muench, David E. ; Grimes, H. Leighton ; Dahl, Richard. / The miR-23a~27a~24-2 microRNA cluster buffers transcription and signaling pathways during hematopoiesis. In: PLoS Genetics. 2017 ; Vol. 13, No. 7.
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AU - Boucher, Austin

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