title: Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming.
abstract: Noncoding microRNAs inhibit translation and lower the transcript stability of coding mRNA, however miR-369 s, in aberrant silencing genomic regions, stabilizes target proteins under cellular stress. We found that in vitro differentiation of embryonic stem cells led to chromatin methylation of histone H3K4 at the miR-369 region on chromosome 12qF in mice, which is expressed in embryonic cells and is critical for pluripotency. Proteomic analyses revealed that miR-369 stabilized translation of pyruvate kinase (Pkm2) splicing factors such as HNRNPA2B1. Overexpression of miR-369 stimulated Pkm2 splicing and enhanced induction of cellular reprogramming by induced pluripotent stem cell factors, whereas miR-369 knockdown resulted in suppression. Furthermore, immunoprecipitation analysis showed that the Argonaute complex contained the fragile X mental retardation-related protein 1 and HNRNPA2B1 in a miR-369-depedent manner. Our findings demonstrate a unique role of the embryonic miR-369-HNRNPA2B1 axis in controlling metabolic enzyme function, and suggest a novel pathway linking epigenetic, transcriptional, and metabolic control in cell reprogramming.
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Konno
authors.affiliation: Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Koseki
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Faculty of Science, Kyushu University, Fukuoka, 819-0395, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Dyah Laksmi
authors.initials: DL
authors.lastname: Dewi
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ozaki
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Noguchi
authors.affiliation: Kyushu University, Department of Molecular and Surgical Oncology, Tsurumihara 4546, Beppu, Ohita, 874-0838, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, 981-1293, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanuma
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, 981-1293, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002135:Calcium-Binding Proteins; D065150:Cellular Reprogramming; D018507:Gene Expression Regulation, Developmental; D006019:Glycolysis; D057809:HEK293 Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007453:Iodide Peroxidase / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D005810:Multigene Family; D014176:Protein Biosynthesis; D034622:RNA Interference
chemical_list: D060565:Argonaute Proteins; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D036341:Intercellular Signaling Peptides and Proteins; C560308:MIRN369 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C439768:hnRNP A2; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase