| Autor: |
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. |
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| Zdroj: |
Science Translational Medicine; 6/19/2019, Vol. 11 Issue 497, p1-11, 11p |
| Abstrakt: |
An epigenetic sclerotic lock: Systemic sclerosis (SSc) is an autoimmune disease resulting in progressive fibrosis of connective tissue for which few therapies are available. Shin et al. found an enhancer whose epigenetic activation led to sustained up-regulation of TGFB2, but not other isoforms of TGFB, in fibroblasts from patients with diffuse SSc. Constitutive activation of TGFβ2 signaling in patient fibroblasts resulted from NF-κB and BRD4 occupancy at the enhancer. Accordingly, treatment with the bromodomain inhibitor JQ1 repressed collagen synthesis and reversed fibrosis in patient skin explants. TGFβ2 signaling may thus be a key, potentially targetable mechanism of fibrosis in some patients with diffuse SSc. 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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