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- Title
Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis.
- Authors
Pachera, Elena; Assassi, Shervin; Salazar, Gloria A.; Stellato, Mara; Renoux, Florian; Wunderlin, Adam; Blyszczuk, Przemyslaw; Lafyatis, Robert; Kurreeman, Fina; de Vries-Bouwstra, Jeska; Messemaker, Tobias; Feghali-Bostwick, Carol A.; Rogler, Gerhard; van Haaften, Wouter T.; Dijkstra, Gerard; Oakley, Fiona; Calcagni, Maurizio; Schniering, Janine; Maurer, Britta; Distler, Jörg H. W.
- 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.
- Subjects
NON-coding RNA; FIBROSIS; EXTRACELLULAR matrix; MYOFIBROBLASTS; GENE expression; RNA metabolism; RESEARCH; FIBROBLASTS; GROWTH factors; ANIMAL experimentation; RESEARCH methodology; RNA; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; RESEARCH funding; PULMONARY fibrosis; EXTRACELLULAR space; CELL lines; CARRIER proteins; MICE
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 9, p4888
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI135439