| First Author | Ghosh AK | Year | 2013 |
| Journal | J Invest Dermatol | Volume | 133 |
| Issue | 5 | Pages | 1302-10 |
| PubMed ID | 23303459 | Mgi Jnum | J:197955 |
| Mgi Id | MGI:5494936 | Doi | 10.1038/jid.2012.479 |
| Citation | Ghosh AK, et al. (2013) p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-beta: epigenetic feed-forward amplification of fibrosis. J Invest Dermatol 133(5):1302-10 |
| abstractText | Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by persistent fibroblast activation triggered by transforming growth factor-beta (TGF-beta). As the acetyltransferase p300 has a key role in fibrosis and its availability governs the intensity of fibrotic responses, we investigated p300 expression in SSc and the molecular basis of its regulation. We found that expression of p300 was markedly elevated in SSc skin biopsies and was induced by TGF-beta in explanted normal skin fibroblasts. Stimulation of p300 by TGF-beta was independent of Smads and involved the early-immediate transcription factor Egr-1 (early growth response 1), a key regulator of profibrotic TGF-beta signaling. Indeed, Egr-1 was both sufficient and necessary for p300 regulation in vitro and in vivo. Increased p300 accumulation in TGF-beta-treated fibroblasts was associated with histone hyperacetylation, whereas p300 depletion, or selective pharmacological blockade of its acetyltransferase activity, attenuated TGF-beta-induced responses. Moreover, TGF-beta enhanced both p300 recruitment and in vivo histone H4 acetylation at the COL1A2 (collagen, type I, alpha2) locus. These findings implicate p300-mediated histone acetylation as a fundamental epigenetic mechanism in fibrogenesis and place Egr-1 upstream in TGF-beta-driven stimulation of p300 gene expression. The results establish a firm link between fibrosis with aberrant p300 expression and epigenetic activity that, to our knowledge, is previously unreported. Targeted disruption of p300-mediated histone acetylation might therefore represent a viable antifibrotic strategy. |
