EKLF/KLF1 coordinates specialized transcriptional networks required to maintain the integrity of terminal erythropoiesis

Erythroid Krüppel Like Factor (EKLF/ KLF1) is a C2H2 zinc finger transcription factor that plays a critical role in all aspects of erythropoiesis. Mutations in KLF1 lead to diverse phenotypes ranging from mild to severe anemias. Patients with a heterozygous E325K mutation (CDA type IV) exhibit impaired erythroid terminal differentiation and increased presence of binucleate erythroblasts. We previously showed that KLF1 is necessary for cell cycle exit and enucleation in mouse primary cells. In the current study we discovered that genes involved in cell motility, cell division, and mitotic pathways are all directly regulated by KLF1. Klf1-/- cells exhibit increased numbers of binucleated erythroblasts and DNA bridges, and differentiating Klf1-/- erythroblasts display an increased percentage of cytokinesis failure events and defective microtubule bundling. Klf1-/- erythroblasts produce frequent aberrant F-actin-rich membrane protrusions and anucleate cell fragments. Human CDA type IV cells exhibit similar patterns of dysregulation of cytokinesis and cell motility genes. Collectively, we show that KLF1 is necessary for maintaining the integrity of erythroid cell divisions by direct regulation of genes involved in cytokinesis and motility pathways during terminal erythroid differentiation.