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

• DOI: 10.1128/mcb.06643-11
• Publication Date: 2012-05-30T03:57:16Z
• Authors: Imari Mimura; Masaomi Nangaku; Yasuharu Kanki; Shuichi Tsutsumi; Tsuyoshi Inoue; Takahide Kohro; Shogo Yamamoto; Takanori Fujita; Teppei Shimamura; Jun-ichi Suehiro; Akashi Taguchi; Mika Kobayashi; Kyoko Tanimura; Takeshi Inagaki; Toshiya Tanaka; Takao Hamakubo; Juro Sakai; Hiroyuki Aburatani; Tatsuhiko Kodama; Youichiro Wada
• Keywords: 0301 basic medicine; Jumonji Domain-Containing Histone Demethylases; 0303 health sciences; Binding Sites; Glucose Transporter Type 3; Protein Conformation; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; Chromatin; Cell Line; 3. Good health; Histones; 03 medical and health sciences; Human Umbilical Vein Endothelial Cells; Humans; RNA Interference; RNA, Small Interfering

Hypoxia-inducible factor 1 (HIF1) is a master regulator of adaptive gene expression under hypoxia. However, a role for HIF1 in the epigenetic regulation remains unknown. Genome-wide analysis of HIF1 binding sites (chromatin immunoprecipitation [ChIP] with deep sequencing) of 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 conditions by using DNA microarrays. We clarified that early hypoxia-responsive genes are functionally associated with glycolysis, including GLUT3 (SLC2A3). Acetylated lysine 27 of histone 3 covered the HIF1 binding sites, and HIF1 functioned as an enhancer of SLC2A3 by interaction with lysine (K)-specific demethylase 3A (KDM3A). Knockdown of HIF1α and KDM3A showed that glycolytic genes are regulated by both HIF1 and KDM3A and respond to hypoxia in a manner independent of cell type specificity. We elucidated that both the chromatin conformational structure and histone modification change under hypoxic conditions and enhance the expression of SLC2A3 based on the combined results of chromatin conformation capture (3C) and ChIP assays. KDM3A is recruited to the SLC2A3 locus in an HIF1-dependent manner and demethylates H3K9me2 so as to upregulate its expression. These findings provide novel insights into the interaction between HIF1 and KDM3A and also the epigenetic regulation of HIF1.