Project description
Mapping the molecular mechanism for hypoxia
The human body relies on oxygen, but our precise molecular responses to low oxygen states remain unknown. One such mechanism is the release of erythropoietin (EPO), a glycoprotein that stimulates red blood cell production whose structure is partly determined by genetics. By studying individuals with a congenital excess of red blood cells with small structural differences in EPO, the MSCA-funded HYPOXIA project will decipher the splicing and expression pattern of EPO. The project will utilise an innovative cellular disease model to study the differentiation of pluripotent stem cells into erythropoietin-producing cells. These cells will then be analysed using RNA-seq and ATAC-seq approaches. This research has the potential to greatly benefit human health, particularly of those living with pathological haematological conditions.
Objective
Cellular adaptation to oxygen deficiency (hypoxia) is a complex biological process. Germline mutations occurring in the hypoxia genes pathway provided major information to dissect the molecular mechanisms regulating this pathway. The objective of HYPOXIA project is to elucidate the molecular and regulatory mechanisms governing erythropoietin (EPO) gene expression, a major actor of the hypoxia pathway. The originality of HYPOXIA lies in identifying naturally occurring germline EPO mutations in patients with hereditary erythrocytosis presenting excess red blood cells production. Recently, the host laboratory and European collaborators have identified intriguing genetic variants located in non-coding sequences of EPO in six families with erythrocytosis. Remarkably, all families exhibited normal circulating EPO levels, suggesting gain-of-function potentials of the new EPO. EPO is the hormone that regulates daily red blood cells production and its regulation greatly depends on the developmental stage, cellular type, and oxygen concentration. Given the complexity in EPO regulation, HYPOXIA aims at deciphering the expression and splicing mechanism of the newly identified EPO. I will use an innovative cellular disease model based on differentiating human induced pluripotent stem cells (hiPSCs) into different EPO-producing cells (neural crest cells and hepatocytes). The wild-type, edited, and mutant cells will then be studied using Next Generation Sequencing approaches (RNAseq and ATACseq). Besides its erythropoietic role, studies have highlighted various pleiotropic effects of EPO such as its protective role in ischemic injury and wound healing and regulation of metabolic homeostasis including gender-specific EPO response. Thus, HYPOXIA cellular model may lead to the development of new therapeutics or treatments for erythrocytosis, anemia, and other EPO-related disorders. The newly identified EPO isoforms might render this cytokine a promising game changer in human health.
Fields of science
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-AG-UN - HORIZON Unit GrantCoordinator
75654 Paris
France