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11 An Essential Role for the RNA Editor-Exonuclease Axis in Terminal Erythroid Differentiation

Program: Oral and Poster Abstracts
Type: Oral
Session: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Mechanisms and Regulation of Erythropoiesis
Hematology Disease Topics & Pathways:
Biological Processes, erythropoiesis
Saturday, December 5, 2020: 8:30 AM

Areum Han, PhD1,2, Alena V. Yermalovich, PhD2*, Vanessa Lundin, PhD2*, Daniel S. Pearson, MD, PhD2*, Mariam Hachimi, PhD2*, Patricia Sousa2*, Brianna Hilton2*, Michael Morse2*, John Atwater2*, Yosra Zhang2*, Pheobe Hunter2*, Vivian Morris2*, Jihan K. Osborne, PhD2*, Jenna M. Frame, PhD2, Ran Jing, PhD2*, Yu Chung Huang, MD2*, Caroline Kubaczka, PhD2*, Trista E. North, PhD3,4,5, Thorsten Schlaeger, PhD2* and George Q. Daley, MD, PhD2,4

1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA
2Division of Hematology/Oncology, Stem Cell Program, Boston Children's Hospital, Boston, MA
3Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA
4Harvard Medical School, Boston, MA
5Boston Children's Hospital, Boston, MA

Erythropoiesis is an intricate process by which lineage-committed erythroid progenitors become mature red blood cells. Reticulocytes are terminal-staged, immature red blood cells with residual RNA after enucleation. In the absence of pathology, reticulocytes are efficiently processed into mature red blood cells and typically represent a small percentage of cells in human peripheral blood. In contrast, when differentiated in vitro from pluripotent stem cells or CD34+ progenitor cells, red cells tend to arrest at the reticulocyte stage. Recent studies have highlighted that uridylation by Terminal Uridylyl Transferases (TUTases) occurs on a broad spectrum of RNA classes in mammalian cells. Oligo-uridylated RNA is recognized by exoribonucleases and targeted for decay. We posited that the machinery behind RNA degradation that accompanies terminal erythropoiesis might involve RNA tail editors coupled to exonuclease activity. Utilizing constitutional murine knockout models, we observed that blood from the TUTase Zcchc6 RNA editor knockout embryos exhibited reticulocytosis and a terminal maturation defect, as documented by FACS, histology, and hematological profiling. Murine strains deficient in the downstream exonuclease Dis3l2 phenocopied the RNA decay defect of the Zcchc6 KO. Conditional knockout murine models of the TUTase-Dis3l2 axis driven by the red cell specific Erythropoietin Receptor-Cre exhibited comparable phenotypes, suggesting a cell intrinsic and niche-independent role for the TUTase-Dis3l2 axis in promoting red blood cell maturation. We are modulating the expression of this axis by various methods to optimize modeling of hemoglobinopathies such as sickle cell anemia.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH