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Sci Transl Med. 2019 Jun 19;11(497). pii: eaaw0790. doi: 10.1126/scitranslmed.aaw0790.

Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis.

Author information

1
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. hdietz@jhmi.edu jshin50@jhmi.edu.
2
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
5
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
6
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Abstract

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor-β2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFβ2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.

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