title: The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence.
abstract: Oncogene-induced senescence (OIS) can occur in response to oncogenic insults and is considered an important tumour suppressor mechanism. Here we identify the lncRNA MIR31HG as upregulated in OIS and find that knockdown of MIR31HG promotes a strong p16(INK4A)-dependent senescence phenotype. Under normal conditions, MIR31HG is found in both nucleus and cytoplasm, but following B-RAF expression MIR31HG is located mainly in the cytoplasm. We show that MIR31HG interacts with both INK4A and MIR31HG genomic regions and with Polycomb group (PcG) proteins, and that MIR31HG is required for PcG-mediated repression of the INK4A locus. We further identify a functional enhancer, located between MIR31HG and INK4A, which becomes activated during OIS and interacts with the MIR31HG promoter. Data from melanoma patients show a negative correlation between MIR31HG and p16(INK4A) expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16(INK4A).
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.
authors.forename: Marta
authors.initials: M
authors.lastname: Montes
authors.affiliation: Department of Molecular Medicine, Århus University Hospital, Skejby, Århus N 8200, Denmark.
authors.forename: Morten M
authors.initials: MM
authors.lastname: Nielsen
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.
authors.forename: Giulia
authors.initials: G
authors.lastname: Maglieri
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Jacobsen
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Højfeldt
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal-Singh
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Kristian
authors.identifier: http://orcid.org/0000-0003-1975-6097
authors.initials: K
authors.lastname: Helin
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam 3015 CN, The Netherlands.
authors.forename: Harmen J G
authors.initials: HJG
authors.lastname: van de Werken
authors.affiliation: Department of Molecular Medicine, Århus University Hospital, Skejby, Århus N 8200, Denmark.|Bioinformatics Research Center, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.
authors.forename: Anders H
authors.identifier: http://orcid.org/0000-0002-7407-3398
authors.initials: AH
authors.lastname: Lund
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D009857:Oncogenes; D010641:Phenotype; D063146:Polycomb-Group Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D063146:Polycomb-Group Proteins; D062085:RNA, Long Noncoding; D048493:Proto-Oncogene Proteins B-raf