The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2

Nat Commun. 2018 Jan 16;9(1):237. doi: 10.1038/s41467-017-02431-1.


Impaired or excessive growth of endothelial cells contributes to several diseases. However, the functional involvement of regulatory long non-coding RNAs in these processes is not well defined. Here, we show that the long non-coding antisense transcript of GATA6 (GATA6-AS) interacts with the epigenetic regulator LOXL2 to regulate endothelial gene expression via changes in histone methylation. Using RNA deep sequencing, we find that GATA6-AS is upregulated in endothelial cells during hypoxia. Silencing of GATA6-AS diminishes TGF-β2-induced endothelial-mesenchymal transition in vitro and promotes formation of blood vessels in mice. We identify LOXL2, known to remove activating H3K4me3 chromatin marks, as a GATA6-AS-associated protein, and reveal a set of angiogenesis-related genes that are inversely regulated by LOXL2 and GATA6-AS silencing. As GATA6-AS silencing reduces H3K4me3 methylation of two of these genes, periostin and cyclooxygenase-2, we conclude that GATA6-AS acts as negative regulator of nuclear LOXL2 function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / metabolism*
  • Animals
  • Cell Adhesion Molecules / genetics
  • Cyclooxygenase 2 / genetics
  • Endothelial Cells / metabolism*
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition
  • GATA6 Transcription Factor / genetics*
  • Gene Expression Regulation / genetics*
  • Gene Silencing
  • Histone Code / genetics
  • Histones / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia / genetics*
  • In Vitro Techniques
  • Methylation
  • Mice
  • Neovascularization, Physiologic / genetics*
  • RNA, Antisense / genetics*
  • RNA, Long Noncoding / genetics*


  • Cell Adhesion Molecules
  • GATA6 Transcription Factor
  • GATA6 protein, human
  • Histones
  • POSTN protein, human
  • RNA, Antisense
  • RNA, Long Noncoding
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Amino Acid Oxidoreductases
  • LOXL2 protein, human