The studies conducted previously have demonstrated that the expression of several lysine (K)-specific demethylases (KDMs) is hypoxia induced. This study aims to investigate the precise mechanisms fundamental to this regulation and its practical implications for endothelial cell function, such as angiogenesis.

The expression changes of KDMs under hypoxia and modulation of HIF (hypoxia-inducible factor) expression were analyzed using  RNA-Seq and GRO-Seq in endothelial cells. Evidence suggests that most KDMs are induced at the level of nascent transcription mediated by the action of HIF-2α and HIF-1α. The transcriptional changes at the initiation level represented the primary mechanism of the gene activation. It was found that redistribution of H3K27me3 at approximately 2000-3000 transcriptionally active loci nearby genes implicated in angiogenesis. Furthermore, this study demonstrated that the vascular endothelial growth factor A (VEGFA) expression is partly induced by KDM6B-and KDM4B-mediated demethylation of nearby regions. These findings provide new insights into the regulation of VEGFA-mediated angiogenesis and the regulation of KDMs via hypoxia.

In conclusion, this study describes an added level of epigenetic regulation where hypoxia induces redistribution of H3K27me3 around genes implicated in angiogenesis and proliferation and. The demonstration of KDM6B and KDM4B was also achieved, which played a vital role in modulating the expression of the major angiogenic driver VEGFA.