title: Adenosine-to-inosine RNA editing by ADAR1 is essential for normal murine erythropoiesis.
abstract: Adenosine deaminases that act on RNA (ADARs) convert adenosine residues to inosine in double-stranded 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 microRNA levels were found in ADAR1-deficient erythroid cells. Using an editing-deficient allele, we demonstrate that RNA editing is the essential function of ADAR1 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.
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Liddicoat
authors.affiliation: Taconic Biosciences, Cologne, Germany; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Stem Cell Program, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Jochen C
authors.initials: JC
authors.lastname: Hartner
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Piskol
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Gokul
authors.initials: G
authors.lastname: Ramaswami
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Alistair M
authors.initials: AM
authors.lastname: Chalk
authors.affiliation: Center for Pediatric Biomedical Research, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kingsley
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Stem Cell Program, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
authors.affiliation: Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Wall
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Heidelberg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeburg
authors.affiliation: Center for Pediatric Biomedical Research, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: James
authors.initials: J
authors.lastname: Palis
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Stem Cell Program, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Jin Billy
authors.initials: JB
authors.lastname: Li
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia. Electronic address: cwalkley@svi.edu.au.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
mesh_terms: D000241:Adenosine / Q000235:genetics*; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016000:Cluster Analysis; D004909:Erythrocyte Indices; D041905:Erythroid Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006098:Granulocytes / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D007288:Inosine / Q000235:genetics*; D007372:Interferons / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D038042:Myelopoiesis / Q000235:genetics; D009928:Organ Specificity; D010641:Phenotype; D017393:RNA Editing; D016601:RNA-Binding Proteins / Q000235:genetics; D017471:Receptors, Interferon / Q000378:metabolism; D018626:Retroelements; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; D016601:RNA-Binding Proteins; D017471:Receptors, Interferon; D018626:Retroelements; D007288:Inosine; D007372:Interferons; C000599465:ADAR1 protein, mouse; D000243:Adenosine Deaminase; D000241:Adenosine