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Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis
  1. Marlene Krämer1,
  2. Clara Dees1,
  3. Jingang Huang1,
  4. Inga Schlottmann1,
  5. Katrin Palumbo-Zerr1,
  6. Pawel Zerr1,
  7. Kolja Gelse2,
  8. Christian Beyer1,
  9. Alfiya Distler1,
  10. Victor E Marquez3,
  11. Oliver Distler4,
  12. Georg Schett1,
  13. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Orthopaedic Trauma Surgery, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
  4. 4Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen D-91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives Epigenetic modifications such as DNA methylation and histone acetylation have been implicated in the pathogenesis of systemic sclerosis. However, histone methylation has not been investigated so far. We therefore aimed to evaluate the role of the trimethylation of histone H3 on lysine 27 (H3K27me3) on fibroblast activation and fibrosis.

Methods H3K27me3 was inhibited by 3-deazaneplanocin A (DZNep) in cultured fibroblasts and in two murine models of dermal fibrosis. Fibrosis was analysed by assessment of the dermal thickening, determination of the hydroxyproline content and by quantification of the numbers of myofibroblasts. The expression of fos-related antigen 2 (fra-2) was assessed by real-time PCR, western blot and immunohistochemistry and modulated by siRNA.

Results Inhibition of H3K27me3 stimulated the release of collagen in cultured fibroblasts in a time and dose-dependent manner. Treatment with DZNep exacerbated fibrosis induced by bleomycin or by overexpression of a constitutively active transforming growth factor β receptor type I. Moreover, treatment with DZNep alone was sufficient to induce fibrosis. Inhibition of H3K27me3 induced the expression of the profibrotic transcription factor fra-2 in vitro and in vivo. Knockdown of fra-2 completely prevented the profibrotic effects of DZNep.

Conclusions These data demonstrate a novel role of H3 Lys27 histone methylation in fibrosis. In contrast to other epigenetic modifications such as DNA methylation and histone acetylation, H3 Lys27 histone methylation acts as a negative regulator of fibroblast activation in vitro and in vivo by repressing the expression of fra-2.

  • Fibroblasts
  • Systemic Sclerosis
  • Inflammation

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