title: ZFP36L1 promotes monocyte/macrophage differentiation by repressing CDK6.
abstract: RNA binding proteins (RBPs)-mediated post-transcriptional control has been implicated in influencing various aspects of RNA metabolism and playing important roles in mammalian development and pathological diseases. However, the functions of specific RBPs and the molecular mechanisms through which they act in monocyte/macrophage differentiation remain to be determined. In this study, through bioinformatics analysis and experimental validation, we identify that ZFP36L1, a member of ZFP36 zinc finger protein family, exhibits significant decrease in acute myeloid leukemia (AML) patients compared with normal controls and remarkable time-course increase during monocyte/macrophage differentiation of PMA-induced THP-1 and HL-60 cells as well as induction culture of CD34(+) hematopoietic stem/progenitor cells (HSPCs). Lentivirus-mediated gain and loss of function assays demonstrate that ZFP36L1 acts as a positive regulator to participate in monocyte/macrophage differentiation. Mechanistic investigation further reveals that ZFP36L1 binds to the CDK6 mRNA 3'untranslated region bearing adenine-uridine rich elements and negatively regulates the expression of CDK6 which is subsequently demonstrated to impede the in vitro monocyte/macrophage differentiation of CD34(+) HSPCs. Collectively, our work unravels a ZFP36L1-mediated regulatory circuit through repressing CDK6 expression during monocyte/macrophage differentiation, which may also provide a therapeutic target for AML therapy.
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Ming-Tai
authors.initials: MT
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.affiliation: Haematology Department, the 303 Hospital, Nanning, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Haematology Department, the 303 Hospital, Nanning, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Yin
authors.affiliation: Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital to Academy of Military Medical Science, Beijing, China.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Ning
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Shen
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Yan-Ni
authors.initials: YN
authors.lastname: Ma
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Hua-Lu
authors.initials: HL
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: The State Key Laboratory of Medical Molecular Biology and the Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Jun-Wu
authors.initials: JW
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D018952:Antigens, CD34 / Q000378:metabolism; D051817:Butyrate Response Factor 1 / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D057809:HEK293 Cells; D018922:HL-60 Cells; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D018952:Antigens, CD34; D051817:Butyrate Response Factor 1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C102034:ZFP36L1 protein, human; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6