Epigenetic Modifications: A Strategy for Systemic Sclerosis
Epigenetic Modifications: A Strategy for Systemic Sclerosis
Epigenetic modifications of gene expression comprise modifications of DNA by DNA methylation and modifications of the histone proteins by acetylation, methylation, SUMOylation or phosphorylation. DNA methylation in the promoter region of genes represses gene transcription. Histone modifications influence the structure of DNA and regulate gene expression by changing the availability of DNA for the transcriptional machinery or DNA-binding proteins. Histone modifications are mediated by enzymes and induce or repress gene expression. Aberrant expression of single enzymes disturb the normal balance of these modifiers leading to cancer or autoimmune diseases. We show in this article that epigenetic modifications contribute to the massive production of extracellular matrix proteins in systemic sclerosis skin fibroblasts. Both DNA methylation and histone modifications contribute to the activated phenotype of systemic sclerosis fibroblasts. In vitro and in vivo experiments demonstrate that the use of epigenetic-based drugs on these cells is able to reverse their activated phenotype.
Systemic sclerosis (SSc) is a chronic autoimmune disease resulting in immune activation, fibrosis of the skin and internal organs, and damage of small blood vessels. Fibrosis is the main histopathological hallmark in established SSc, and organ fibrosis is among the leading causes of death in these patients. While there are therapeutic advances for the vascular manifestations of SSc such as pulmonary hypertension and fingertip ulcers, the treatment or even prevention of organ fibrosis remains a major challenge. Thus, the identification of molecules and key cascades, which are crucial for the progression of fibrosis in SSc and which are candidates for molecular targeted therapies, are a major focus of current SSc research. The potential molecular targets for therapy have been recently reviewed extensively and include, among others, tyrosine kinases, TGF-β, peroxisome proliferator-activated receptor-γ, proteasomes, src kinases, IL-13, rho-associated kinases, cannabinoid receptor 2, adenosine A2A receptor and connective tissue growth factor. In this article we focus on epigenetic modifications as novel strategies for therapeutic intervention in this often devastating disease.
Abstract and Introduction
Abstract
Epigenetic modifications of gene expression comprise modifications of DNA by DNA methylation and modifications of the histone proteins by acetylation, methylation, SUMOylation or phosphorylation. DNA methylation in the promoter region of genes represses gene transcription. Histone modifications influence the structure of DNA and regulate gene expression by changing the availability of DNA for the transcriptional machinery or DNA-binding proteins. Histone modifications are mediated by enzymes and induce or repress gene expression. Aberrant expression of single enzymes disturb the normal balance of these modifiers leading to cancer or autoimmune diseases. We show in this article that epigenetic modifications contribute to the massive production of extracellular matrix proteins in systemic sclerosis skin fibroblasts. Both DNA methylation and histone modifications contribute to the activated phenotype of systemic sclerosis fibroblasts. In vitro and in vivo experiments demonstrate that the use of epigenetic-based drugs on these cells is able to reverse their activated phenotype.
Introduction
Systemic sclerosis (SSc) is a chronic autoimmune disease resulting in immune activation, fibrosis of the skin and internal organs, and damage of small blood vessels. Fibrosis is the main histopathological hallmark in established SSc, and organ fibrosis is among the leading causes of death in these patients. While there are therapeutic advances for the vascular manifestations of SSc such as pulmonary hypertension and fingertip ulcers, the treatment or even prevention of organ fibrosis remains a major challenge. Thus, the identification of molecules and key cascades, which are crucial for the progression of fibrosis in SSc and which are candidates for molecular targeted therapies, are a major focus of current SSc research. The potential molecular targets for therapy have been recently reviewed extensively and include, among others, tyrosine kinases, TGF-β, peroxisome proliferator-activated receptor-γ, proteasomes, src kinases, IL-13, rho-associated kinases, cannabinoid receptor 2, adenosine A2A receptor and connective tissue growth factor. In this article we focus on epigenetic modifications as novel strategies for therapeutic intervention in this often devastating disease.