An in vivo functional screen uncovers miR-150-mediated regulation of hematopoietic injury response.
Hematopoietic stem and progenitor cells are often undesired targets of chemotherapies, leading to hematopoietic suppression requiring careful clinical management. Whether microRNAs control hematopoietic injury response is largely unknown. We report an in vivo gain-of-function screen and the identification of miR-150 as an inhibitor of hematopoietic recovery upon 5-fluorouracil-induced injury. Utilizing a bone marrow transplant model with a barcoded microRNA library, we screened for barcode abundance in peripheral blood of recipient mice before and after 5-fluorouracil treatment. Overexpression of screen-candidate miR-150 resulted in significantly slowed recovery rates across major blood lineages, with associated impairment of bone marrow clonogenic potential. Conversely, platelets and myeloid cells from miR-150 null marrow recovered faster after 5-fluorouracil treatment. Heterozygous knockout of c-myb, a conserved target of miR-150, partially phenocopied miR-150-forced expression. Our data highlight the role of microRNAs in controlling hematopoietic injury response and demonstrate the power of in vivo functional screens for studying microRNAs in normal tissue physiology.
Department of Genetics, Yale Stem Cell Center, Yale Cancer Center and Yale Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
Brian D
BD
Adams
Shangqin
S
Guo
Haitao
H
Bai
Yanwen
Y
Guo
Cynthia M
CM
Megyola
Jijun
J
Cheng
Kartoosh
K
Heydari
Changchun
C
Xiao
E Premkumar
EP
Reddy
Jun
J
Lu
D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D002478:Cells, Cultured; D005472:Fluorouracil / Q000633:toxicity; D020869:Gene Expression Profiling; D015723:Gene Library; D006410:Hematopoiesis; D006579:Heterozygote; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing
D035683:MicroRNAs; C529101:Mirn150 microRNA, mouse; D020598:Proto-Oncogene Proteins c-myb; D005472:Fluorouracil