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 Distler; Gabriela Kania; Mojca Frank-Bertoncelj; Oliver Distler

doi:10.1172/JCI135439

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 journal › Article › Academic › peer-review

38 Citations (Scopus)

34 Downloads (Pure)

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 language	English
Pages (from-to)	4888-4905
Number of pages	18
Journal	CLIN Journal
Volume	130
Issue number	9
DOIs	https://doi.org/10.1172/JCI135439
Publication status	Published - 1-Sept-2020

Keywords

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

Access to Document

10.1172/JCI135439

Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosisFinal publisher's version, 6.49 MBLicence: Taverne

Handle.net

Persistent link

Cite this

Pachera, E., Assassi, S., Salazar, G. A., Stellato, M., Renoux, F., Wunderlin, A., Blyszczuk, P., Lafyatis, R., Kurreeman, F., de Vries-Bouwstra, J., Messemaker, T., Feghali-Bostwick, C. A., Rogler, G., van Haaften, W. T., Dijkstra, G., Oakley, F., Calcagni, M., Schniering, J., Maurer, B., ... Distler, O. (2020). Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis. CLIN Journal, 130(9), 4888-4905. https://doi.org/10.1172/JCI135439

@article{7bfd370149774d83a507bdef11d168fe,

title = "Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis",

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.",

keywords = "GROWTH-FACTOR-BETA, SYSTEMIC-SCLEROSIS, EXPRESSION PATTERNS, CARDIAC FIBROSIS, GENES, CLASSIFICATION, HETEROGENEITY, ENCYCLOPEDIA, FIBROBLASTS, METASTASIS",

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

year = "2020",

month = sep,

day = "1",

doi = "10.1172/JCI135439",

language = "English",

volume = "130",

pages = "4888--4905",

journal = "CLIN Journal",

issn = "0021-9738",

publisher = "AMER SOC CLINICAL INVESTIGATION INC",

number = "9",

}

Pachera, E, Assassi, S, Salazar, GA, Stellato, M, Renoux, F, Wunderlin, A, Blyszczuk, P, Lafyatis, R, Kurreeman, F, de Vries-Bouwstra, J, Messemaker, T, Feghali-Bostwick, CA, Rogler, G, van Haaften, WT , Dijkstra, G, Oakley, F, Calcagni, M, Schniering, J, Maurer, B, Distler, JH, Kania, G, Frank-Bertoncelj, M & Distler, O 2020, 'Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis', CLIN Journal, vol. 130, no. 9, pp. 4888-4905. https://doi.org/10.1172/JCI135439

TY - JOUR

T1 - Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis

AU - Pachera, Elena

AU - Assassi, Shervin

AU - Salazar, Gloria A

AU - Stellato, Mara

AU - Renoux, Florian

AU - Wunderlin, Adam

AU - Blyszczuk, Przemyslaw

AU - Lafyatis, Robert

AU - Kurreeman, Fina

AU - de Vries-Bouwstra, Jeska

AU - Messemaker, Tobias

AU - Feghali-Bostwick, Carol A

AU - Rogler, Gerhard

AU - van Haaften, Wouter T

AU - Dijkstra, Gerard

AU - Oakley, Fiona

AU - Calcagni, Maurizio

AU - Schniering, Janine

AU - Maurer, Britta

AU - Distler, Jörg Hw

AU - Kania, Gabriela

AU - Frank-Bertoncelj, Mojca

AU - Distler, Oliver

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

KW - GROWTH-FACTOR-BETA

KW - SYSTEMIC-SCLEROSIS

KW - EXPRESSION PATTERNS

KW - CARDIAC FIBROSIS

KW - GENES

KW - CLASSIFICATION

KW - HETEROGENEITY

KW - ENCYCLOPEDIA

KW - FIBROBLASTS

KW - METASTASIS

U2 - 10.1172/JCI135439

DO - 10.1172/JCI135439

M3 - Article

C2 - 32603313

SN - 0021-9738

VL - 130

SP - 4888

EP - 4905

JO - CLIN Journal

JF - CLIN Journal

IS - 9

ER -