Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis
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 J, Kania G, Frank-Bertoncelj M, Distler O (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 130
Pages Range: 4888-4905
Journal Issue: 9
DOI: 10.1172/JCI135439
Abstract
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.
Authors with CRIS profile
Involved external institutions
Universitätsspital Zürich (USZ)
Switzerland (CH)
University of Texas Health Science Center at Houston (UTHealth)
United States (USA) (US)
University of Pittsburgh
United States (USA) (US)
Leiden University Medical Center
Netherlands (NL)
Medical University of South Carolina (MUSC)
United States (USA) (US)
University of Groningen / Rijksuniversiteit Groningen
Netherlands (NL)
Newcastle University
United Kingdom (GB)
Switzerland (CH)
University of Texas Health Science Center at Houston (UTHealth)
United States (USA) (US)
University of Pittsburgh
United States (USA) (US)
Leiden University Medical Center
Netherlands (NL)
Medical University of South Carolina (MUSC)
United States (USA) (US)
University of Groningen / Rijksuniversiteit Groningen
Netherlands (NL)
Newcastle University
United Kingdom (GB)
How to cite
APA:
Pachera, E., Assassi, S., Salazar, G.A., Stellato, M., Renoux, F., Wunderlin, A.,... Distler, O. (2020). Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis. Journal of Clinical Investigation, 130(9), 4888-4905. https://doi.org/10.1172/JCI135439
MLA:
Pachera, Elena, et al. "Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis." Journal of Clinical Investigation 130.9 (2020): 4888-4905.
BibTeX: Download