Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis

Elena Pachera, Shervin Assassi, Gloria A Salazar, Mara Stellato, Florian Renoux, Adam Wunderlin, Przemyslaw Blyszczuk, Robert Lafyatis, Fina Kurreeman, Jeska de Vries-Bouwstra, Tobias Messemaker, Carol A Feghali-Bostwick, Gerhard Rogler, Wouter T van Haaften, Gerard Dijkstra, Fiona Oakley, Maurizio Calcagni, Janine Schniering, Britta Maurer, Jörg Hw DistlerGabriela Kania, Mojca Frank-Bertoncelj, Oliver Distler

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4888-4905
Number of pages18
JournalCLIN Journal
Volume130
Issue number9
DOIs
Publication statusPublished - 1-Sep-2020

Keywords

  • GROWTH-FACTOR-BETA
  • SYSTEMIC-SCLEROSIS
  • EXPRESSION PATTERNS
  • CARDIAC FIBROSIS
  • GENES
  • CLASSIFICATION
  • HETEROGENEITY
  • ENCYCLOPEDIA
  • FIBROBLASTS
  • METASTASIS

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