title: Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis.
abstract: Systemic sclerosis (SSc) is manifested by fibrosis, vasculopathy and immune dysregulation. So far, a unifying hypothesis underpinning these pathological events remains unknown. Given that SSc is a multifactorial disease caused by both genetic and environmental factors, we focus on the two transcription factors, which modulate the fibrotic reaction and are epigenetically suppressed in SSc dermal fibroblasts, Friend leukaemia integration 1 (Fli1) and Krüppel-like factor 5 (KLF5). In addition to the Fli1 silencing-dependent collagen induction, the simultaneous knockdown of Fli1 and KLF5 synergistically enhances expression of connective tissue growth factor. Notably, mice with double heterozygous deficiency of Klf5 and Fli1 mimicking the epigenetic phenotype of SSc skin spontaneously recapitulate all the three features of SSc, including fibrosis and vasculopathy of the skin and lung, B-cell activation and autoantibody production. These studies implicate the epigenetic downregulation of Fli1 and KLF5 as a central event triggering the pathogenic triad of SSc.
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Noda
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.affiliation: 1] Department of Cardiovascular Medicine, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [2] Translational Systems Biology and Medicine Initiative, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [3] Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: 1] Department of Cardiovascular Medicine, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [2] Translational Systems Biology and Medicine Initiative, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Fujiu
authors.affiliation: Department of Cardiovascular Medicine, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Saigusa
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kaname
authors.initials: K
authors.lastname: Akamata
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toyama
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-cho, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuruta
authors.affiliation: Arthritis Center, Rheumatology, Boston University School of Medicine, 72 East Concord St, E-5, Boston, Massachusetts 02118, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojanowska
authors.affiliation: 1] Department of Cardiovascular Medicine, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [2] Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001808:Blood Vessels / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D003094:Collagen / Q000819:agonists / Q000235:genetics / Q000276:immunology; D055513:Connective Tissue Growth Factor / Q000819:agonists / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D001323:Autoantibodies; C078433:FLI1 protein, human; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D051789:Proto-Oncogene Protein c-fli-1; D034741:RNA, Small Interfering; D055513:Connective Tissue Growth Factor; D003094:Collagen