Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

Joseph Yusup Shin, James Daniel Beckett, Rustam Bagirzadeh, Tyler J. Creamer, Ami A. Shah, Zsuzsanna McMahan, Julie J. Paik, Margaret M. Sampedro, Elena G. MacFarlane, Michael A. Beer, Daniel Warren, Fredrick M. Wigley, Harry C. Dietz

Research output: Contribution to journalArticle

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-kB 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.

Original languageEnglish (US)
Article numbereaaw0790
JournalScience translational medicine
Volume11
Issue number497
DOIs
StatePublished - Jan 1 2019

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Systemic Scleroderma
Epigenomics
Fibrosis
Skin
Autocrine Communication
Viscera
NF-kappa B
Transforming Growth Factors
Gene Expression Profiling
Chromatin
Fibroblasts
Cytokines
Gene Expression
Inhibition (Psychology)

ASJC Scopus subject areas

  • Medicine(all)

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Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis. / Shin, Joseph Yusup; Beckett, James Daniel; Bagirzadeh, Rustam; Creamer, Tyler J.; Shah, Ami A.; McMahan, Zsuzsanna; Paik, Julie J.; Sampedro, Margaret M.; MacFarlane, Elena G.; Beer, Michael A.; Warren, Daniel; Wigley, Fredrick M.; Dietz, Harry C.

In: Science translational medicine, Vol. 11, No. 497, eaaw0790, 01.01.2019.

Research output: Contribution to journalArticle

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AU - McMahan, Zsuzsanna

AU - Paik, Julie J.

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