title: p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis.
abstract: 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.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Farina
authors.forename: Jianxiu
authors.initials: J
authors.lastname: Yu
authors.forename: Bayar
authors.initials: B
authors.lastname: Thimmapaya
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000328:Adult; D000818:Animals; D001706:Biopsy; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D024042:Collagen Type I; D051766:Early Growth Response Protein 1; D006657:Histones; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C497325:EGR1 protein, human; C486109:Egr1 protein, mouse