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

Abstract

• miR-29a maintains HSC function by targeting Dnmt3a.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 restores HSPC 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. (Blood. 2015;125(14):2206-2216

Dnmt3a-mediated inhibition of Wnt in cardiac progenitor cells improves differentiation and remote remodeling after infarction

“…In addition, the functional importance of both Dnmt3a and miR-29a for Wif1 gene methylation and Wif1 expression as well as for CPC differentiation was verified in naive CPCs in monocultures as well as in the coculture model, respectively. Our identification of the miR-29 family based on bioinformatic analysis corroborates previous reports on Dnmt3a regulation by miR-29a in other cell types (27,28) and is supported by our expression as well as miR-29a mimic and inhibition data. Altogether, we demonstrated that miR-29a indirectly modifies the methylation pattern of the Wif1 gene, promoting its expression through Dnmt3a downregulation, which is also key for the effect of miR-29a on differentiation.…”

Cell cycle regulation of hematopoietic stem or progenitor cells

“…Their work also suggested that Dnmt3a may be a target gene of miR-29, thus contributing to the phenotype of miR-29a/b-1-null HSPCs through negative regulation [93]. What is more, other microRNAs can work through different ways, such as miR-33 can control HSCs selfrenewal by mediating the down-regulation of p53 [94], and miR-126 can arrest cell cycle progression of HSC in vitro and in vivo by PI3 K/AKT/GSK3 pathway, increasing HSC proliferation without inducing exhaustion [95,96].…”

“…No defects in HSC [89] MicroRNAs miR-29a Enhanced proliferation of HSPC [92,93] miR-33 Enhanced HSCs self-renewal [94] miR-126 Decreased HSC proliferation [95,96] numbers of HSPCs, decreased HSC self-renewal, and increased HSC cell cycling and apoptosis using homozygous deletion of the miR-29a/b-1, mainly due to loss of miR-29a. Their work also suggested that Dnmt3a may be a target gene of miR-29, thus contributing to the phenotype of miR-29a/b-1-null HSPCs through negative regulation [93].…”

Expression profiling of snoRNAs in normal hematopoiesis and AML

“…MicroRNAs are also expressed in a lineage-specific fashion and have been shown to play key roles in the regulation of hematopoiesis. [2][3][4] Other sncRNAs include small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), small interfering RNAs, and Piwi-interacting RNAs. With some exceptions, the expression of these other sncRNAs in hematopoietic cells and their contribution to the regulation of hematopoiesis are not well characterized.…”