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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
[Available on 2017-10-01]
DOI:
10.1016/j.exphem.2016.06.250
[Indexed for MEDLINE]
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