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Regulation of endothelial gene expression by a long non-coding RNA

January 2018. About 74% of the human genome is transcribed but only about 2% actually account for protein-coding genes. Thus the majority of the human transcriptome can be referred to as non-coding RNA. According to their size, non-coding RNAs are subdivided into small non-coding RNAs (<200 nucleotides) and long non-coding RNAs (lncRNAs; >200 nucleotides). Little is known so far about the latter class although it has emerged that on a functional level lncRNAs are implicated in complex biological processes through diverse mechanisms.

Impaired or excessive growth of endothelial cells contributes to several diseases and it is important to understand the functional involvement of regulatory long non-coding RNAs in these processes. A team of scientists led by Stefanie Dimmeler from the Institute of Cardiovascular Regeneration at Goethe University Frankfurt has identified novel hypoxia-regulated lncRNAs in endothelial cells. The team investigated the molecular mode of action of the lncRNA GATA6-AS (long non-coding antisense transcript of GATA6) and showed that this lncRNA interacts with the epigenetic regulator LOXL2 to regulate endothelial gene expression via changes in histone methylation.

Using RNA deep sequencing, the team found that GATA6-AS is upregulated in endothelial cells during hypoxia. Silencing of GATA6-AS diminished TGF-β2-induced endothelial–mesenchymal transition in vitro and promoted formation of blood vessels in mice. The scientists identified the enyzme LOXL2, known to remove activating H3K4me3 chromatin marks, as a GATA6-AS-associated protein, and revealed a set of angiogenesis-related genes that are inversely regulated by LOXL2 and GATA6-AS silencing. As GATA6-AS silencing reduced H3K4me3 methylation of two of these genes, periostin and cyclooxygenase-2, GATA6-AS must act as negative regulator of nuclear LOXL2 function. More ...


Stefanie Dimmeler, Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Germany, dimmeler@em.uni-frankfurt.de, http://www.cardiovascular-regeneration.com


Neumann P, Jaé N, Knau A, Glaser SF, Fouani Y, Rossbach O, Krüger M, John D, Bindereif A, Grote P, Boon RA, Dimmeler S (2018) The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2. Nat Commun 9: 237. http://dx.doi.org/10.1038/s41467-017-02431-1.