Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming

PLoS One. 2015 Jul 15;10(7):e0132789. doi: 10.1371/journal.pone.0132789. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Argonaute Proteins / metabolism
  • Base Sequence
  • Binding Sites
  • Calcium-Binding Proteins
  • Cellular Reprogramming*
  • Gene Expression Regulation, Developmental
  • Glycolysis
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Iodide Peroxidase / genetics
  • Membrane Proteins / genetics
  • Mice
  • MicroRNAs / physiology*
  • Molecular Sequence Data
  • Mouse Embryonic Stem Cells / metabolism
  • Multigene Family
  • Protein Biosynthesis
  • RNA Interference*

Substances

  • Argonaute Proteins
  • Calcium-Binding Proteins
  • DLK1 protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Intercellular Signaling Peptides and Proteins
  • MIRN369 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • hnRNP A2
  • iodothyronine deiodinase type III
  • Iodide Peroxidase

Grants and funding

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (http://www.mext.go.jp/english/; #23390199, #25112708, #25134711, #30253420, #26670604; M.M., K.M., H.I.); a Grant-in-Aid from the Ministry of Health, Labor and Welfare (http://www.mhlw.go.jp/english/; #H23-003; M.M., H.I.); a grant from the National Institute of Biomedical Innovation (http://www.nibio.go.jp/english/index.html; #12-4; M.M., H.I.); and a grant from the Osaka University Drug Discovery Funds (http://www.osaka-u.ac.jp/en/index.html; M.M., H.I.). Partial support was received from Takeda Science and Medical Research Foundation (http://www.takeda-sci.or.jp/index.html; M.M., H.I.), Princess Takamatsu Cancer Research Fund (http://www.ptcrf.or.jp/english; M.M., H.I.), Suzuken Memorial Foundation (http://www.suzukenzaidan.or.jp; M.K.), Yasuda Medical Foundation (http://www.yasuda-mf.or.jp; N.N.), Pancreas Research Foundation (http://www.jprf.or.jp/shoreisho.html; K.K.), Nakatani Foundation (http://www.nakatani-foundation.jp; H.I.), and Nakatomi Foundation of Japan (https://www.nakatomi.or.jp/en/index.html; M.K.). Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd. (http://www.taiho.co.jp/english/), Evidence Based Medical (EBM) Research Center (http://ebmrce.co.jp/index.html), Chugai Co., Ltd. (http://www.chugai-pharm.co.jp/english/index.html), Yakult Honsha Co., Ltd. (http://www.yakult.co.jp/english/index.html), and Merck Co., Ltd. (http://www.merck.co.jp/en/index.html); those funders had no role in main experimental equipments, supplies expenses, study design, data collection and analysis, decision to publish, or preparation of the manuscript, in this work.