Genetic and molecular basis of Adaptive and Mal‐adaptive excessive erythropoietic responses in the Andean region

Abstract

RationaleExcessive Erythrocytosis (EE) is a predominant trait in some high‐altitude dwellers (Chronic Mountain Sickness, CMS, or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human “experiment in nature” and studied both populations (with CMS and without, non‐CMS). This population provides a unique opportunity to study both adaptive (non‐CMS) and mal‐adaptive (CMS) mechanism(s) and understand the molecular basis of regulating erythropoiesis at high altitude.MethodsIn order to understand the molecular basis for polycythemia of high altitude, we generated a disease in‐the dish‐model by re‐programming fibroblasts from CMS and non‐CMS subjects. In the past, we have discovered that there are selective sweeps that seem to be statistically different between CMS and non‐CMS and hence contain candidate genes. In this study, by manipulating expression of these candidate genes (Eg. SENP1, ARID1B) in our in‐vitro model system, we delineate the molecular mechanism(s) of the CMS polycythemia as well adaptive response to suppress the excessive response in non‐CMS subjects.ResultsAs compared to sea level controls who responded to hypoxia by increasing their RBCs modestly, CMS cells increased theirs remarkably (up to 60 fold) with a dose‐dependent response to graded hypoxia (1.5, 5, 10% O2). Non‐CMS cells showed a blunted increase in RBC production under hypoxia. In order to understand the genetic basis of these phenotypes, we knocked down SENP1 (a desumoylase) in CMS iPS cells using lentiviral constructs and observed a striking reduction (>90%) of the CMS excessive erythropoietic response to low O2. Similarly, by knocking down ARID1B (subunit of a SWI/SNF chromatin remodeling complex) in non‐CMS we observed that RBC formation increased significantly under hypoxia. Our recent results suggest a critical role of ARID1B at the chromatin level in regulating erythroid transcriptional factors such as GATA1.Conclusion. Our results demonstrate the presence of a regulatory system (SENP1 and ARID1B) that is critical in erythropoiesis and that is out of balance in the CMS subjects and tightly regulated in adapted non‐CMS subjects. Our results indicate that SENP1 and ARID1B both regulate GATA1 levels albeit through unique mechanism(s) in CMS patients as well as adapted non‐CMS subjects. Therefore, studying both populations is essential in understanding the erythropoietic response under hypoxia at high altitude.