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

J Clin Invest. 2020 Sep 1;130(9):4888-4905. doi: 10.1172/JCI135439.


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.

Keywords: Autoimmune diseases; Autoimmunity; Cell Biology; Epigenetics; Fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix / pathology
  • Humans
  • Mice
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*


  • Adaptor Proteins, Signal Transducing
  • DDIT4L protein, human
  • Ddit4l protein, mouse
  • RNA, Long Noncoding
  • Transforming Growth Factor beta