Hypoxia-mediated regulation of histone demethylases affects angiogenesis associated functions in endothelial cells

ABSTRACT: Purpose: Jumonji-containing (jmjC) family of proteins are involved in epigenetic gene regulation through histone specific lysine demethylation. Previous studies have demonstrated that the expression of several members of this family is induced by hypoxia. However, the mechanisms by which lysine specific demethylases (KDMs) are regulated under hypoxia and how they affect angiogenesis, the primary method to restore blood oxygen, remains unknown. In this study, we characterized regulation of KDMs using a combination of nascent and mature mRNA profiling. Furthermore, we aimed to identify KDMs that play a role in mediating the VEGF-mediated angiogenic response in endothelial cells. Results: We demonstrated that majority of KDMs were induced by hypoxia and this effect is more prominent upon constitutive activation of HIF2α compared to HIF1α. Half of the changes in mRNAs levels were attributed to transcriptional regulation as evidenced by similar changes at the level of nascent mRNAs, whereas half was likely due to post-transcriptional mechanisms affecting mature mRNA levels. Hypoxia induced genome-wide redistribution of H3K27me3 at 2000 transcriptionally active loci in human umbilical vein endothelial cells (HUVECs). Among these, we further verified the induction of VEGF-A by demethylation of the locus by KDM4B and KDM6B in response to hypoxia. Accordingly, knockdown of KDM4B and KDM6B led to decreased proliferation and tube formation of HUVECs. Conclusions: Hypoxia leads to both transcriptional and post-transcriptional induction of KDMs and wide redistribution of H3K27me3 at active chromatin regions. Main mediator of angiogenesis, VEGFA, is regulated by KDM4B- and KDM6B- mediated demethylation in HUVECs with functional implications for cell proliferation and tube formation. These findings provide novel insights into the regulation of KDMs by hypoxia and the epigenetic regulation of angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139678 | GEO | 2020/09/03

REPOSITORIES: GEO