| p300 Is Elevated in Systemic Sclerosis and Its Expression Is Positively Regulated by TGF-β: Epigenetic Feed-Forward Amplification of Fibrosis. | |
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MedLine Citation:
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PMID: 23303459 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by persistent fibroblast activation triggered by transforming growth factor-β (TGF-β). 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-β in explanted normal skin fibroblasts. Stimulation of p300 by TGF-β was independent of Smads and involved the early-immediate transcription factor Egr-1 (early growth response 1), a key regulator of profibrotic TGF-β signaling. Indeed, Egr-1 was both sufficient and necessary for p300 regulation in vitro and in vivo. Increased p300 accumulation in TGF-β-treated fibroblasts was associated with histone hyperacetylation, whereas p300 depletion, or selective pharmacological blockade of its acetyltransferase activity, attenuated TGF-β-induced responses. Moreover, TGF-β enhanced both p300 recruitment and in vivo histone H4 acetylation at the COL1A2 (collagen, type I, α2) locus. These findings implicate p300-mediated histone acetylation as a fundamental epigenetic mechanism in fibrogenesis and place Egr-1 upstream in TGF-β-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.Journal of Investigative Dermatology advance online publication, 10 January 2013; doi:10.1038/jid.2012.479. |
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Authors:
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Asish K Ghosh; Swati Bhattacharyya; Robert Lafyatis; Giuseppina Farina; Jianxiu Yu; Bayar Thimmapaya; Jun Wei; John Varga |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-10 |
Journal Detail:
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Title: The Journal of investigative dermatology Volume: - ISSN: 1523-1747 ISO Abbreviation: J. Invest. Dermatol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0426720 Medline TA: J Invest Dermatol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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