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Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosis
- Source :
- J Clin Invest, Journal of Clinical Investigation, 130(9), 4888-4905. AMER SOC CLINICAL INVESTIGATION INC, CLIN Journal, 130(9), 4888-4905. AMER SOC CLINICAL INVESTIGATION INC
- Publication Year :
- 2020
- Publisher :
- American Society for Clinical Investigation, 2020.
-
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.
- 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
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 130
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....cb021339e09a4327eabd341197408b4f