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Lookup NU author(s): Professor Fiona OakleyORCiD
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© 2020, American Society for Clinical Investigation.TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of the DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of TGF-β-induced ECM remodeling and fibrosis. Copyright:
Author(s): Pachera E, Assassi S, Salazar GA, Stellato M, Renoux F, Wunderlin A, Blyszczuk P, Lafyatis R, Kurreeman F, De Vries-Bouwstra J, Messemaker T, Feghali-Bostwick CA, Rogler G, Van Haaften WT, Dijkstra G, Oakley F, Calcagni M, Schniering J, Maurer B, Distler JHW, Kania G, Frank-Bertoncelj M, Distler O
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Year: 2020
Volume: 130
Issue: 9
Pages: 4888-4905
Print publication date: 01/09/2020
Online publication date: 30/06/2020
Acceptance date: 17/06/2020
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: https://doi.org/10.1172/JCI135439
DOI: 10.1172/JCI135439
PubMed id: 32603313
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