Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosis
Elena Pachera, … , Mojca Frank-Bertoncelj, Oliver Distler
Elena Pachera, … , Mojca Frank-Bertoncelj, Oliver Distler
Published June 30, 2020
Citation Information: J Clin Invest. 2020;130(9):4888-4905. https://doi.org/10.1172/JCI135439.
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Research Article Autoimmunity Cell biology

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

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

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 H.W. Distler, Gabriela Kania, Mojca Frank-Bertoncelj, Oliver Distler

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Figure 1

H19X is upregulated in skin from patients with SSc from different cohorts in a variety of fibrotic disorders and in physiological DW healing.

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H19X is upregulated in skin from patients with SSc from different cohort...
Heatmap showing 20 most significantly deregulated lncRNA in skin derived from patients with SSc as revealed by RNA-Seq analysis; H19X is indicated by the arrow (cohort 1) (A). H19X differential expression in SSc versus HC skin in the PRESS cohort (B), and cohort 3 (C), as measured by RNA-Seq. H19X differential expression as measured by qPCR in cohort 4, normalized to GAPDH and RPLP0 (D). H19X differential expression in ILD-SSc versus HC lung as measured by qPCR with normalization to GAPDH and RPLP0 (E). H19X differential expression in IPF (F), Crohn’s disease (G), PSC (H), and DWs measured by qPCR with normalization to GAPDH and RPLP0 (I). Data are presented as single values and median. Differential expression analysis was carried out on variance stabilized counts using DEseq2 package 44 (A–C). Mann-Whitney test (D–F and I). Kruskal–Wallis test (G and H). *P < 0.05, **P < 0.01, ***P < 0.001.