1. Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosis
- Author
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Oliver Distler, Fiona Oakley, Shervin Assassi, Wouter T. van Haaften, Britta Maurer, Maurizio Calcagni, Mojca Frank-Bertoncelj, Jörg H W Distler, Gloria Salazar, Gabriela Kania, Janine Schniering, Fina A S Kurreeman, Robert Lafyatis, Jeska K de Vries-Bouwstra, Carol Feghali-Bostwick, Florian Renoux, Mara Stellato, E. Pachera, Tobias Messemaker, Gerard Dijkstra, Przemyslaw Blyszczuk, Adam Wunderlin, Gerhard Rogler, Translational Immunology Groningen (TRIGR), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
0301 basic medicine ,FIBROBLASTS ,GENES ,Cardiac fibrosis ,Pulmonary Fibrosis ,Biology ,CLASSIFICATION ,Cell Line ,Extracellular matrix ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mediator ,Transforming Growth Factor beta ,Fibrosis ,Gene expression ,medicine ,Animals ,Humans ,Gene silencing ,EXPRESSION PATTERNS ,HETEROGENEITY ,CARDIAC FIBROSIS ,Myofibroblasts ,Enhancer ,Adaptor Proteins, Signal Transducing ,GROWTH-FACTOR-BETA ,SYSTEMIC-SCLEROSIS ,General Medicine ,medicine.disease ,ENCYCLOPEDIA ,Extracellular Matrix ,3. Good health ,Cell biology ,Chromatin ,030104 developmental biology ,030220 oncology & carcinogenesis ,METASTASIS ,RNA, Long Noncoding ,Research Article - Abstract
TGF-beta 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-beta-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-beta, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-beta-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-beta-induced ECM remodeling and fibrosis.
- Published
- 2020