Erythropoietin production in embryonic neural cells is controlled by hypoxia-inducible factors and histone deacetylases in an undifferentiated state

Abstract

AbstractDuring mammalian development, production sites of the erythroid growth factor erythropoietin (EPO) shift from the neural tissues to the liver in embryos and to the adult kidneys. Embryonic neural EPO-producing (NEP) cells, a subpopulation of neuroepithelial and neural crest cells, express theEpogene between embryonic day (E) 8.5 and E11.5 to promote primitive erythropoiesis in mice. WhileEpogene expression in the liver and kidney is induced under hypoxic conditions through hypoxia-inducible transcription factor (HIF) 2α, theEpogene regulatory mechanisms in NEP cells remain to be elucidated. This study confirms the presence of cells coexpressing the genes encoding EPO and HIF2α in E9.5 neural tubes, where the hypoxic microenvironment activates HIF1α. In human neural progenitors and mouse embryonic neural tissues, a HIF-activating compound upregulatedEPOexpression, and this induction was blocked by inhibiting HIFs. Additionally, a cell line of NEP cell derivatives that no longer expressed theEpogene demonstrated that histone deacetylase inhibitors (HDACIs) reactivate EPO production while rejuvenating the cells. HDACIs also inducedEPOgene expression in SK-N-BE(2)c human neuroblastoma cells and mouse primary neural crest cells. Thus, EPO production is controlled by epigenetic mechanisms and hypoxia signaling in an immature state of hypoxic NEP cells.