Erythropoiesis at the crossroad of TGF-beta signaling, epigenetic and mitochondrial dynamics. – ZEBERY

Erythroid differentiation is an essential and continuous process leading to the production of red blood cells. Anemia is a major health problem in humans with ~6-8% of the world population carrying an allele that is deleterious for red blood cell function in a homozygous state. How production of RBCs is achieved in vivo is currently unclear, and how the signaling pathways, metabolic activities and (epi)genetic functions underlying this process are properly coordinated remains poorly characterized. We were the first to show that the TGF-beta pathway and its antagonist (TGF-beta1 and GDF11, respectively) are key effectors of RBC production, and we recently identified through genome-wide and functional assays novel transcription factors, related to this pathway, at the control of RBC production. Importantly, our recent data link this regulatory axis to the control of mitochondrial activity. We wish to investigate how signaling and epigenetic features interconnect with mitochondrial activity to control terminal erythroid differentiation in normal and pathological conditions. Our consortium assembles experts in normal & pathological erythropoiesis, metabolism and epigenetics to address these questions. We will deploy molecular approaches, in vivo models and high throughput assays to provide a deep characterization of the molecular mechanisms controlling terminal erythroid differentiation with the aim to identify novel regulators and test their involvement in ineffective erythropoiesis in pathological conditions such as beta-thalassemia and sickle cell anemias, two of the most common genetic disorders in humans worldwide.