| Autor: |
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 |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Sci Transl Med |
| ISSN: |
1946-6242 |
| Popis: |
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 pro-fibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of nuclear factor kappa-B (NF-kB) or bromodomain-containing protein 4 (BRD4) achieved sustained inhibition of TGFB2 enhancer activity, mitigated pro-fibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest an epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major pro-fibrotic cytokine. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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