Research of the Month

January 2018

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

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

Neumann P*, Jaé N*, Knau A, Glaser SF, Fouani Y, Rossbach O, Krüger M, John D, Bindereif A, Grote P, Boon RA, Dimmeler S. *authors contributed equally to this work

High-throughput sequencing-based profiling of 15 different cell lines revealed that ~74% of the human genome is transcribed, however, only ~2% actually account for protein-coding genes. As a consequence, the majority of the human genome can be referred to as non-coding RNA. Among them, one class of mainly unannotated and uncharacterized non-coding RNAs are the so called long non-coding RNAs (lncRNAs). On a functional level, lncRNAs are implicated in complex biological processes through diverse mechanisms as for example gene regulation, splicing alteration, sponging of microRNAs and recruitment of chromatin modifying enzymes.

Regarding the cardiovascular field, several recent studies identified lncRNAs that control endothelial cell functions and therefore making them as potential targets for the development of therapeutics, since impaired or excessive growth of endothelial cells contributes to several diseases. In the current work the authors showed 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, they found 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. They further identified 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 reduces H3K4me3 methylation of two of these genes, periostin and cyclooxygenase-2, they conclude that GATA6-AS acts as negative regulator of nuclear LOXL2 function. These novel mechanistic insights into the regulation of endothelial cell functions provide new potential therapeutic targets for the treatment of vascular diseases.

 



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