期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 11, 期 497, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaw0790
关键词
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资金
- Scleroderma Research Foundation
- Howard Hughes Medical Institute
- NIH R01 [R01AR068379, R01HG007348]
- Staurulakis Family Discovery Fund
- NIH U01 [U01HG009380]
- NIH [P30 CA006973]
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-beta 2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGF beta 2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-kappa B 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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