Dynamic Change of Chromatin Conformation in Response to Hypoxia Enhances the Expression of GLUT3 (SLC2A3) by Cooperative Interaction of Hypoxia-Inducible Factor 1 and KDM3A

Abstract

HIF1 is a master regulator of the adaptive gene expression to hypoxia. However, a role of HIF1 in the epigenetic regulation remains unknown. Genome-wide analysis of HIF1 binding sites (ChIP-seq) in endothelial cells clarified that HIF1 mainly binds to the intergenic regions distal from transcriptional starting sites under both normoxia and hypoxia. Next we examined the temporal profile of gene expression under hypoxic condition using DNA microarrays. We clarified that early hypoxia responsive genes are functionally associated with glycolysis including GLUT3 (SLC2A3). H3K27ac covered the HIF1 binding sites and HIF1 functions as enhancers of SLC2A3 by interaction with lysine (K)-specific demethylase 3A (KDM3A). Knockdown of HIF1α and KDM3A showed that glycolytic genes were regulated by both HIF1 and KDM3A and responded to hypoxia an independent manner of cell-type specificity. We elucidated that the chromatin conformational structure and histone modification change under hypoxic condition and enhance the expression of SLC2A3 by a combination of chromatin conformation capture (3C) and ChIP assays. KDM3A is recruited to the SLC2A3 loci in an HIF1 dependent manner and demethylates H3K9me2 so as to up-regulate its expression. These findings provide novel insights into the interaction between HIF1 and KDM3A and also the epigenetic regulation of HIF1.