Abstract
Background: Congenital dyserythropoietic anemia type I (CDA-I) is an autosomal recessive disorder marked by ineffective erythropoiesis, abnormal morphology of bone marrow erythroblasts, and iron overload. Most cases of CDA-I are caused by mutations in the CDAN1 gene, which encodes a ubiquitous protein of unknown function, Codanin-1. Methods: To investigate the role of Codanin-1 in the molecular pathways involved in CDA-I, we developed erythroid models using human K562 cells and primary human CD34 + cells from mobilized peripheral blood. Results: Here we show that Codanin-1 expression is required for erythroid progenitor development and normal erythroid cell differentiation. Erythroid cells lacking Codanin-1 demonstrated morphologic changes similar to those observed in CDA-I. Global gene expression changes after Codanin-1 knockdown revealed alterations in a set of key erythroid genes. In particular, the AHSP gene, which showed reduced mRNA and protein expression levels after Codanin-1 knockdown, also demonstrated increased Codanin-1 occupancy at its gene regulatory region by chromatin immunoprecipitation coupled to high-throughput sequencing. Conclusion: In summary, using cell models recapitulating many features of CDA-I, we have studied and confirmed the importance of Codanin-1 during erythroid differentiation and provide mechanistic insight into how loss of Codanin-1 expression results in CDA-I.