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Nat Commun. 2014 Dec 12;5:5797. doi: 10.1038/ncomms6797.

Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis.

Author information

1
Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
2
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.
3
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.
4
Department of Cardiovascular Medicine, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
5
Department of Dermatology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-cho, Abeno-ku, Osaka 545-8585, Japan.
6
Arthritis Center, Rheumatology, Boston University School of Medicine, 72 East Concord St, E-5, Boston, Massachusetts 02118, USA.
7
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.

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.

PMID:
25504335
PMCID:
PMC4268882
DOI:
10.1038/ncomms6797
[Indexed for MEDLINE]
Free PMC Article

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