Han, A.; Yermalovich, A.; Najia, M. A. T.; Pearson, D. S.; Fujiwara, Y.; Bolgov, M.; Kubaczka, C.; North, T. E.; Lundin, V.; Orkin, S.; Daley, G. Q.

Selective RNA degradation during terminal erythropoiesis results in a globin-rich transcriptome in mature erythrocytes, but the specific RNA decay pathways remain unknown. We found that deficiency of the terminal uridylyl transferase enzyme Zcchc6 and the 3\'-5\' exoribonuclease Dis3l2 in mouse models led to fetal and perinatal reticulocytosis, an accumulation of RNA-rich precursors of terminal erythroid cells, suggesting their crucial roles in terminal red cell differentiation. Notably, knockout embryos exhibited persistent high-level expression of Hbb bh1 globin, the ortholog of human fetal {gamma}-globin. Perturbation of the Zcchc6-Dis3l2 pathway in mice engineered to express the human b-globin locus likewise increased {gamma}-globin levels in fetal erythroid cells, suggesting that globin switching entails post transcriptional mechanisms of mRNA destabilization in addition to transcriptional down-regulation. We cultured human hematopoietic stem and progenitor cells (HSPCs), performed CRISPR/Cas9-mediated knockout of ZCCHC6 and DIS3L2, and observed accumulation of RNA and elevated {gamma}-globin levels in terminal erythroid cells. Our findings reveal a conserved role for the ZCCHC6/DIS3L2 RNA editors in terminal erythropoiesis and demonstrate a posttranscriptional mechanism for {gamma}-globin gene switching, advancing research into in vitro erythrocyte generation and {gamma}-globin stabilization to ameliorate hemoglobinopathies.