Role of long noncoding RNA in hypoxia-induced excessive polycythemia

In this project, we identified and validated the function of a group of hypoxia-responding long noncoding RNA (lncRNAs) in regulating erythropoeisis in CMS or non-CMS subjects. Among them, LINC02228/HIKER (Hypoxia Induced Kinase-mediated Erythropoietic Regulator) impacts erythroid colony production in the CMS cells under hypoxic condition. Mechanistic evaluation reveals that HIKER mediates the erythropoietic response in the CMS cells via CSNK2B (the regulatory subunit of Casein kinase 2) function. Modulating expression of CSNK2B in CMS and non-CMS cells affects their erythropoietic response under hypoxia. CSNK2B inhibition by RNAi or specific CK2 inhibitors decreased the hypoxia-induced EE phenotype in CMS cells. Furthermore, in vivo knockdown of the CSNK2B ortholog in zebrafish resulted in severe hemoglobin defects in the embryos even under normoxic condition, demonstrating its vital role in erythropoiesis. Collectively, our results demonstrate that HIKER is a novel erythroid regulator under hypoxic condition in the CMS cells via CSNK2B function. Our results further show essential role of CSNK2B in regulating erythropoiesis under physiological conditions.