Long Noncoding RNA H19X is a Key Mediator of TGF-β-driven Fibrosis

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2020 Jul 1

PMID 32603313

Citations 36

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

Jorg Hw Distler

Gabriela Kania

Mojca Frank-Bertoncelj

Oliver Distler

Affiliations

Soon will be listed here.

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.

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References

Sauvageau M, Goff L, Lodato S, Bonev B, Groff A, Gerhardinger C . Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife. 2014; 2:e01749. PMC: 3874104. DOI: 10.7554/eLife.01749. View

Jelaska A, Arakawa M, Broketa G, Korn J . Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts. Increased proportion of high collagen-producing cells in systemic sclerosis fibroblasts. Arthritis Rheum. 1996; 39(8):1338-46. DOI: 10.1002/art.1780390811. View

Snowden N, Coupes B, Herrick A, Illingworth K, Jayson M, Brenchley P . Plasma TGF beta in systemic sclerosis: a cross-sectional study. Ann Rheum Dis. 1994; 53(11):763-7. PMC: 1005459. DOI: 10.1136/ard.53.11.763. View

Varga J, Pasche B . Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol. 2009; 5(4):200-6. PMC: 3959159. DOI: 10.1038/nrrheum.2009.26. View

Santiago B, Galindo M, Rivero M, Pablos J . Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts. Arthritis Rheum. 2001; 44(7):1667-76. DOI: 10.1002/1529-0131(200107)44:7<1667::AID-ART291>3.0.CO;2-Y. View

van den Hoogen F, Khanna D, Fransen J, Johnson S, Baron M, Tyndall A . 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013; 72(11):1747-55. DOI: 10.1136/annrheumdis-2013-204424. View

Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Iny Stein T . GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford). 2017; 2017. PMC: 5467550. DOI: 10.1093/database/bax028. View

Fu J, Dong G, Shi H, Zhang J, Ning Z, Bao X . LncRNA MIR503HG inhibits cell migration and invasion via miR-103/OLFM4 axis in triple negative breast cancer. J Cell Mol Med. 2019; 23(7):4738-4745. PMC: 6584514. DOI: 10.1111/jcmm.14344. View

Wang D, Rendon A, Wernisch L . Transcription factor and chromatin features predict genes associated with eQTLs. Nucleic Acids Res. 2013; 41(3):1450-63. PMC: 3561974. DOI: 10.1093/nar/gks1339. View

10.

Hu W, Alvarez-Dominguez J, Lodish H . Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Rep. 2012; 13(11):971-83. PMC: 3492712. DOI: 10.1038/embor.2012.145. View

11.

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

12.

Wei J, Melichian D, Komura K, Hinchcliff M, Lam A, Lafyatis R . Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma?. Arthritis Rheum. 2011; 63(6):1707-17. PMC: 3124699. DOI: 10.1002/art.30312. View

13.

Lafyatis R . Transforming growth factor β--at the centre of systemic sclerosis. Nat Rev Rheumatol. 2014; 10(12):706-19. DOI: 10.1038/nrrheum.2014.137. View

14.

Meng X, Nikolic-Paterson D, Lan H . TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016; 12(6):325-38. DOI: 10.1038/nrneph.2016.48. View

15.

Piccoli M, Gupta S, Viereck J, Foinquinos A, Samolovac S, Kramer F . Inhibition of the Cardiac Fibroblast-Enriched lncRNA Prevents Cardiac Fibrosis and Diastolic Dysfunction. Circ Res. 2017; 121(5):575-583. DOI: 10.1161/CIRCRESAHA.117.310624. View

16.

Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U . The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature. 2014; 505(7485):635-40. DOI: 10.1038/nature12943. View

17.

Varga J, Abraham D . Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007; 117(3):557-67. PMC: 1804347. DOI: 10.1172/JCI31139. View

18.

Li D, Hsu S, Purushotham D, Sears R, Wang T . WashU Epigenome Browser update 2019. Nucleic Acids Res. 2019; 47(W1):W158-W165. PMC: 6602459. DOI: 10.1093/nar/gkz348. View

19.

Fabregat I, Moreno-Caceres J, Sanchez A, Dooley S, Dewidar B, Giannelli G . TGF-β signalling and liver disease. FEBS J. 2016; 283(12):2219-32. DOI: 10.1111/febs.13665. View

20.

Piek E, Ju W, HEYER J, Escalante-Alcalde D, Stewart C, Weinstein M . Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. J Biol Chem. 2001; 276(23):19945-53. DOI: 10.1074/jbc.M102382200. View