Abstract
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.
Highlights
Impaired or excessive growth of endothelial cells contributes to several diseases
To analyze the influence of hypoxia on long non-coding RNAs (lncRNAs) expression in human umbilical vein endothelial cells (HUVECs), we performed deep sequencing of ribo-minus RNA isolated from cells that were exposed to hypoxic (12 and 24 h, 0.2% O2) or normoxic conditions
After filtering data for long non-coding RNA annotation, expression levels, and significant response to hypoxia, we identified 54 transcripts to be upregulated and 10 to be downregulated upon 24 h of hypoxia (Fig. 1a, Supplementary Table 1)
Summary
Impaired or excessive growth of endothelial cells contributes to several diseases. the functional involvement of regulatory long non-coding RNAs in these processes is not well defined. We show that the long non-coding antisense transcript of GATA6 (GATA6AS) interacts with the epigenetic regulator LOXL2 to regulate endothelial gene expression via changes in histone methylation. Hypoxia was shown to regulate the long non-coding RNAs LINC00323 and MIR503HG and silencing of these transcripts led to angiogenic defects in vitro[13]. Another vascular enriched long non-coding RNA, SENCR, was found to control the angiogenic capacity of human umbilical vein endothelial cells (HUVECs) by regulating endothelial gene expression[14]. We determine the influence of hypoxia on lncRNA expression in HUVECs, and provide mechanistic insights into the epigenetic regulation of endothelial gene expression and angiogenesis by the interplay between the chromatin modifying enzyme LOXL2 and its negative regulator, the lncRNA GATA6-AS
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