MiR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a

Wenhuo Hu, James Dooley, Stephen S. Chung, Dhruva Chandramohan, Luisa Cimmino, Siddhartha Mukherjee, Christopher E. Mason, Bart De Strooper, Adrian Liston, Christopher Y. Park

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Hematopoietic stem cells (HSCs) possess the ability to generate all hematopoietic cell types and to self-renew over long periods, but the mechanisms that regulate their unique properties are incompletely understood. Herein, we show that homozygous deletion of the miR-29a/b-1 bicistron results in decreased numbers of hematopoietic stem and progenitor cells (HSPCs), decreased HSC self-renewal, and increased HSC cell cycling and apoptosis. The HSPC phenotype is specifically due to loss of miR-29a, because miR-29b expression is unaltered in miR-29a/b-1- null HSCs, and only ectopic expression of miR-29a restoresHSPC function both in vitro and in vivo. HSCs lacking miR-29a/b-1 exhibit widespread transcriptional dysregulation and adopt gene expression patterns similar to normal committed progenitors. A number of predicted miR-29 target genes, including Dnmt3a, are significantly upregulated in miR-29a/b-1-null HSCs. The loss of negative regulation of Dnmt3a by miR-29a is a major contributor to the miR-29a/b-1-null HSPC phenotype, as both in vitro Dnmt3a short hairpin RNA knockdown assays and a genetic haploinsufficiency model of Dnmt3a restored the frequency and long-term reconstitution capacity of HSCs from miR-29a/b-1-deficient mice. Overall, these data demonstrate that miR-29a is critical for maintaining HSC function through its negative regulation of Dnmt3a.

Original languageEnglish (US)
Pages (from-to)2206-2216
Number of pages11
JournalBlood
Volume125
Issue number14
DOIs
StatePublished - Apr 2 2015

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Hu, W., Dooley, J., Chung, S. S., Chandramohan, D., Cimmino, L., Mukherjee, S., Mason, C. E., De Strooper, B., Liston, A., & Park, C. Y. (2015). MiR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a. Blood, 125(14), 2206-2216. https://doi.org/10.1182/blood-2014-06-585273