Adenosine-to-inosine RNA editing by ADAR1 is essential for normal murine erythropoiesis

Adenosine deaminases that act on RNA (ADARs) convert adenosine residues to inosine in doublestranded RNA. In vivo, ADAR1 is essential for the maintenance of hematopoietic stem/progenitors. Whether other hematopoietic cell types also require ADAR1 has not been assessed. Using erythroid- and myeloid-restricted deletion of Adar1, we demonstrate that ADAR1 is dispensable for myelopoiesis but is essential for normal erythropoiesis. Adar1-deficient erythroid cells display a profound activation of innate immune signaling and high levels of cell death. No changes in microRNAlevels were found inADAR1-deficient erythroid cells. Using an editing-deficient allele, we demonstrate thatRNA editing is the essential function ofADAR1 during erythropoiesis.Mapping of adenosine-to-inosine editing in purified erythroid cells identified clusters of hyperedited adenosines located in long 3’-untranslated regions of erythroid-specific transcripts and these are ADAR1-specific editing events. ADAR1-mediated RNA editing is essential for normal erythropoiesis