title: miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a.
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 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.
authors: Human Oncology and Pathogenesis Program, Sloan-Kettering Cancer Center, New York, NY;
authors: Wenhuo
authors: W
authors: Hu
authors: Autoimmune Genetics Laboratory, Vlaams Interuniversitair Instituut Voor Biotechnologie, Leuven, Belgium; Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium;
authors: James
authors: J
authors: Dooley
authors: Human Oncology and Pathogenesis Program, Sloan-Kettering Cancer Center, New York, NY; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
authors: Stephen S
authors: SS
authors: Chung
authors: Department of Physiology and Biophysics, Weill-Cornell Medical College, New York, NY;
authors: Dhruva
authors: D
authors: Chandramohan
authors: School of Medicine and Howard Hughes Medical Institute, New York University, New York, NY;
authors: Luisa
authors: L
authors: Cimmino
authors: Department of Medicine, Division of Oncology, Columbia University Medical Center, New York, NY;
authors: Siddhartha
authors: S
authors: Mukherjee
authors: Department of Physiology and Biophysics, Weill-Cornell Medical College, New York, NY;
authors: Christopher E
authors: CE
authors: Mason
authors: Vlaams Interuniversitair Instituut Voor Biotechnologie, Center for the Biology of Disease, Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium; and.
authors: Bart
authors: B
authors: de Strooper
authors: Autoimmune Genetics Laboratory, Vlaams Interuniversitair Instituut Voor Biotechnologie, Leuven, Belgium; Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium;
authors: Adrian
authors: A
authors: Liston
authors: Human Oncology and Pathogenesis Program, Sloan-Kettering Cancer Center, New York, NY; Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Christopher Y
authors: CY
authors: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D000090205:DNA Methyltransferase 3A; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
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