title: An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis.
abstract: The Ten-Eleven-Translocation 2 (TET2) gene, which oxidates 5-methylcytosine in DNA to 5-hydroxylmethylcytosine (5hmC), is a key tumor suppressor frequently mutated in hematopoietic malignancies. However, the molecular regulation of TET2 expression is poorly understood. We show that TET2 is under extensive microRNA (miRNA) regulation, and such TET2 targeting is an important pathogenic mechanism in hematopoietic malignancies. Using a high-throughput 3' UTR activity screen, we identify >30 miRNAs that inhibit TET2 expression and cellular 5hmC. Forced expression of TET2-targeting miRNAs in vivo disrupts normal hematopoiesis, leading to hematopoietic expansion and/or myeloid differentiation bias, whereas coexpression of TET2 corrects these phenotypes. Importantly, several TET2-targeting miRNAs, including miR-125b, miR-29b, miR-29c, miR-101, and miR-7, are preferentially overexpressed in TET2-wild-type acute myeloid leukemia. Our results demonstrate the extensive roles of miRNAs in functionally regulating TET2 and cellular 5hmC and reveal miRNAs with previously unrecognized oncogenic potential. Our work suggests that TET2-targeting miRNAs might be exploited in cancer diagnosis.
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Department of Cell Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Shangqin
authors.initials: S
authors.lastname: Guo
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mastriano
authors.affiliation: Wadsworth Center, New York State Department of Health, 150 New Scotland Avenue, Albany, NY 12201, USA.
authors.forename: Chaochun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: D'Alessio
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Eriona
authors.initials: E
authors.lastname: Hysolli
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Megyola
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Roden
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Department of Cell Biology and Genetics, Shantou University Medical College, Guangdong 515041, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Zhou
authors.affiliation: Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Kartoosh
authors.initials: K
authors.lastname: Heydari
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
authors.forename: In-Hyun
authors.initials: IH
authors.lastname: Park
authors.affiliation: Wadsworth Center, New York State Department of Health, 150 New Scotland Avenue, Albany, NY 12201, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.|Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
mesh_terms: D020413:3' Untranslated Regions; D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D015536:Down-Regulation; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C541081:TET2 protein, human