RT Journal Article
SR Electronic
T1 Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 614
OP 620
DO 10.1136/annrheumdis-2012-201615
VO 72
IS 4
A1 Marlene Krämer
A1 Clara Dees
A1 Jingang Huang
A1 Inga Schlottmann
A1 Katrin Palumbo-Zerr
A1 Pawel Zerr
A1 Kolja Gelse
A1 Christian Beyer
A1 Alfiya Distler
A1 Victor E Marquez
A1 Oliver Distler
A1 Georg Schett
A1 Jörg H W Distler
YR 2013
UL http://ard.bmj.com/content/72/4/614.abstract
AB 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.