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Exp Hematol. 2016 Oct;44(10):947-63. doi: 10.1016/j.exphem.2016.06.250. Epub 2016 Jul 1.

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

Author information

1
St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
2
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.
3
Department of Genetics, Stanford University, Stanford, CA, USA.
4
Center for Pediatric Biomedical Research, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
5
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.
6
Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
7
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Heidelberg, Germany.
8
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.
9
Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT, USA.
10
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.

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.

PMID:
27373493
PMCID:
PMC5035604
DOI:
10.1016/j.exphem.2016.06.250
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

disclosure J.C.H. was a paid employee of Taconic Biosciences. Taconic Bioscience had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining authors declare no competing financial interests.

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