title: Survivin controls biogenesis of microRNA in smokers: A link to pathogenesis of rheumatoid arthritis.
abstract: MicroRNAs (miRs) represent a part of epigenetic control of autoimmunity gaining increasing attention in rheumatoid arthritis (RA). Since cigarette smoking plays important role in RA pathogenesis and reprograms transcriptional profile of miRNAs, we ask if the onco-protein survivin, a novel biomarker of RA, may provide a link between smoking and miRNA. Studying survivin expression in leukocytes of 144 female RA patients we observed that smoking patients had higher survivin transcription and a remarkable spreading of survivin isoforms. This was associated with restricted pattern and low production of miRs. Additionally, miRNA processing enzymes Dicer and DGRC8 were decreased in the patients with survivin isoform spreading. The direct contribution of survivin in miRs biogenesis was confirmed by a massive increase of miRs production following inhibition of survivin in leukocyte cultures. Dicer is shown to mediate these effects of survivin. Chromatin immunoprecipitation analysis demonstrated binding of survivin to the Dicer promoter region. Dicer expression increased 5-folds following survivin inhibition. Taken together, this study presents experimental evidence of a novel cellular function of survivin, control of miRs biogenesis. Up-regulation of survivin in smokers suggests its role as effector of the adverse epigenetic control in RA.
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden. Electronic address: karin.andersson@rheuma.gu.se.
authors.forename: Karin M E
authors.initials: KM
authors.lastname: Andersson
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden. Electronic address: minnaturkkila@outlook.com.
authors.forename: Minna
authors.initials: M
authors.lastname: Turkkila
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden. Electronic address: malin.erlandsson@gu.se.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 424, 405 30 Gothenburg, Sweden. Electronic address: apostolos.bossios@lungall.gu.se.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Bossios
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden. Electronic address: sofia.silfversward@rheuma.gu.se.
authors.forename: Sofia Töyrä
authors.initials: ST
authors.lastname: Silfverswärd
authors.affiliation: Center for Neurologic Diseases, Brigham&Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, US. Electronic address: dan_hu@rics.bwh.harvard.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 424, 405 30 Gothenburg, Sweden. Electronic address: linda.ekerljung@lungall.gu.se.
authors.forename: Linda
authors.initials: L
authors.lastname: Ekerljung
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 424, 405 30 Gothenburg, Sweden. Electronic address: carina.malmhall@lungall.gu.se.
authors.forename: Carina
authors.initials: C
authors.lastname: Malmhäll
authors.affiliation: Center for Neurologic Diseases, Brigham&Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, US. Electronic address: hweiner@rics.bwh.harvard.edu.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 424, 405 30 Gothenburg, Sweden. Electronic address: bo.lundback@gu.se.
authors.forename: Bo
authors.initials: B
authors.lastname: Lundbäck
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden. Electronic address: maria.bokarewa@rheuma.gu.se.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000235:genetics*; D000073865:Cigarette Smoking / Q000009:adverse effects / Q000235:genetics*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics; D000074285:Smokers; D000077022:Survivin; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D035683:MicroRNAs; D020033:Protein Isoforms; D000077022:Survivin
keywords: Dicer; Rheumatoid arthritis; Smoking; Survivin; miRNA