An In Vivo Functional Screen Uncovers miR-150-Mediated Regulation of Hematopoietic Injury Response
Brian D. Adams,
Shangqin Guo,
Haitao Bai,
Yanwen Guo,
Cynthia M. Megyola,
Jijun Cheng,
Kartoosh Heydari,
Changchun Xiao,
E. Premkumar Reddy,
Jun Lu
Affiliations
Brian D. Adams
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
Shangqin Guo
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
Haitao Bai
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
Yanwen Guo
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
Cynthia M. Megyola
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
Jijun Cheng
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
Kartoosh Heydari
Department of Immunobiology, Yale Flow Cytometry Core Facility, Yale University, New Haven, CT 06520, USA
Changchun Xiao
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
E. Premkumar Reddy
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA
Jun Lu
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
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.
