title: Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis.
abstract: Periodontitis is affecting over half of the adult population, and represents a major public health problem. Previously, we isolated a subset of gingival fibroblasts (GFs) from periodontitis patients, designated as periodontitis-associated fibroblasts (PAFs), which were highly capable of collagen degradation. To elucidate their molecular profiles, GFs isolated form healthy and periodontitis-affected gingival tissues were analyzed by CAGE-seq and integrated with the FANTOM5 atlas. GFs from healthy gingival tissues displayed distinctive patterns of CAGE profiles as compared to fibroblasts from other organ sites and characterized by specific expression of developmentally important transcription factors such as BARX1, PAX9, LHX8, and DLX5. In addition, a novel long non-coding RNA associated with LHX8 was described. Furthermore, we identified DLX5 regulating expression of the long variant of RUNX2 transcript, which was specifically active in GFs but not in their periodontitis-affected counterparts. Knockdown of these factors in GFs resulted in altered expression of extracellular matrix (ECM) components. These results indicate activation of DLX5 and RUNX2 via its distal promoter represents a unique feature of GFs, and is important for ECM regulation. Down-regulation of these transcription factors in PAFs could be associated with their property to degrade collagen, which may impact on the process of periodontitis.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Division for Health Service Promotion, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Horie
authors.affiliation: Department of Biochemistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.|Division of Functional Morphology Dental Research Center Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Division for Health Service Promotion, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.affiliation: Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Lizio
authors.affiliation: Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: Division of Genomic Technologies (DGT), RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: Alistair R R
authors.initials: AR
authors.lastname: Forrest
authors.affiliation: Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: Department of Microbiology, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima, Fukushima 960-1295, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suzutani
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Center for Cardiovascular Research (CCR), Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.affiliation: Department of Immunology, Genetics and Pathology, Akademiska Sjukhuset, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
authors.affiliation: Department of Biochemistry, Ohu University School of Pharmaceutical Sciences, Misumido 31-1, Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ohshima
mesh_terms: D002478:Cells, Cultured; D016000:Cluster Analysis; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005881:Gingiva / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D009928:Organ Specificity; D010518:Periodontitis / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D059368:RNA Isoforms; D022661:RNA, Untranslated / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C100596:DLX5 protein, human; D018398:Homeodomain Proteins; D059368:RNA Isoforms; D022661:RNA, Untranslated; C493709:RUNX2 protein, human; D014157:Transcription Factors