Hypoxia controls Flvcr1 gene expression in Caco2 cells through HIF2α and ETS1

The tissue-specific gene expression changes mediated by the hypoxia inducible factors (HIFs) allow the adaptation of cells to low oxygen tension and control several processes including erythropoiesis, angiogenesis and vasculogenesis. The Feline Leukemia Virus, subgroup C, Receptor 1 (Flvcr1) gene encodes for two isoforms, Flvcr1a and 1b, involved in the export of heme out of the cell and of mitochondria respectively. Studies in mouse models demonstrated a crucial role of Flvcr1 isoforms in erythropoiesis and during embryo development. Here, we showed the modulation of Flvcr1 gene expression in different tissues and cell lines in response to hypoxia. Chromatin immunoprecipitation analysis demonstrated that HIF2α and HIF-dependent transcription factor ETS1 (v-ets avian erythroblastosis virus E26 oncogene homolog 1) bind at the region -318/+39 of the Flvcr1 promoter. Analysis of Caco2 cells in which HIF2α or ETS1 were silenced or overexpressed demonstrated that, both HIF2α and ETS1 are involved in the transcriptional regulation of Flvcr1a and that HIF2α is absolutely required for Flvcr1a induction upon hypoxia. The inclusion of the Flvcr1 gene in the group of HIF2α-responsive genes strengthens its role in hypoxia-stimulated processes like erythropoiesis, vasculogenesis and heme absorption.