title: PU.1-Regulated Long Noncoding RNA lnc-MC Controls Human Monocyte/Macrophage Differentiation through Interaction with MicroRNA 199a-5p.
abstract: Long noncoding RNAs (lncRNAs) are emerging as important regulators in mammalian development, but little is known about their roles in monocyte/macrophage differentiation. Here we identified a long noncoding monocytic RNA (lnc-MC) that exhibits increased expression during monocyte/macrophage differentiation of THP-1 and HL-60 cells as well as CD34(+) hematopoietic stem/progenitor cells (HSPCs) and is transcriptionally activated by PU.1. Gain- and loss-of-function assays demonstrate that lnc-MC promotes monocyte/macrophage differentiation of THP-1 cells and CD34(+) HSPCs. Mechanistic investigation reveals that lnc-MC acts as a competing endogenous RNA to sequester microRNA 199a-5p (miR-199a-5p) and alleviate repression on the expression of activin A receptor type 1B (ACVR1B), an important regulator of monocyte/macrophage differentiation. We also noted a repressive effect of miR-199a-5p on lnc-MC expression and function, but PU.1-dominant downregulation of miR-199a-5p weakens the role of miR-199a-5p in the reciprocal regulation between miR-199a-5p and lnc-MC. Altogether, our work demonstrates that two PU.1-regulated noncoding RNAs, lnc-MC and miR-199a-5p, have opposing roles in monocyte/macrophage differentiation and that lnc-MC facilitates the differentiation process, enhancing the effect of PU.1, by soaking up miR-199a-5p and releasing ACVR1B expression. Thus, we reveal a novel regulatory mechanism, comprising PU.1, lnc-MC, miR-199a-5p, and ACVR1B, in monocyte/macrophage differentiation.
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ming-Tai
authors.initials: MT
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hai-Shuang
authors.initials: HS
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yan-Ni
authors.initials: YN
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hua-Lu
authors.initials: HL
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Medical Molecular Biology and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China junwu_zhang@pumc.edu.cn.
authors.forename: Jun-Wu
authors.initials: JW
authors.lastname: Zhang
mesh_terms: D030201:Activin Receptors, Type I / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D057809:HEK293 Cells; D018922:HL-60 Cells; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000166:cytology*; D035683:MicroRNAs / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015534:Trans-Activators / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D030201:Activin Receptors, Type I; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D062085:RNA, Long Noncoding; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C531408:mirn199 microRNA, human; C498932:ACVR1B protein, human