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Mol Cell. 2018 Jan 18;69(2):265-278.e6. doi: 10.1016/j.molcel.2017.12.027.

Dual Strategies for Argonaute2-Mediated Biogenesis of Erythroid miRNAs Underlie Conserved Requirements for Slicing in Mammals.

Author information

1
Department of Developmental Biology, Sloan Kettering Institute, 1275 York Ave., Box 252, New York, NY 10065, USA; Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
2
Department of Molecular Pharmacology, Sloan Kettering Institute, 1275 York Ave., New York, NY 10065, USA.
3
Department of Microbiology and Immunology, UCSF Diabetes Center, Keck Center for Noncoding RNA, University of California San Francisco, San Francisco, CA 94143, USA.
4
Department of Developmental Biology, Sloan Kettering Institute, 1275 York Ave., Box 252, New York, NY 10065, USA.
5
Department of Developmental Biology, Sloan Kettering Institute, 1275 York Ave., Box 252, New York, NY 10065, USA; Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA. Electronic address: laie@mskcc.org.

Abstract

While Slicer activity of Argonaute is central to RNAi, conserved roles of slicing in endogenous regulatory biology are less clear, especially in mammals. Biogenesis of erythroid Dicer-independent mir-451 involves Ago2 catalysis, but mir-451-KO mice do not phenocopy Ago2 catalytic-dead (Ago2-CD) mice, suggesting other needs for slicing. Here, we reveal mir-486 as another dominant erythroid miRNA with atypical biogenesis. While it is Dicer dependent, it requires slicing to eliminate its star strand. Thus, in Ago2-CD conditions, miR-486-5p is functionally inactive due to duplex arrest. Genome-wide analyses reveal miR-486 and miR-451 as the major slicing-dependent miRNAs in the hematopoietic system. Moreover, mir-486-KO mice exhibit erythroid defects, and double knockout of mir-486/451 phenocopies the cell-autonomous effects of Ago2-CD in the hematopoietic system. Finally, we observe that Ago2 is the dominant-expressed Argonaute in maturing erythroblasts, reflecting a specialized environment for processing slicing-dependent miRNAs. Overall, the mammalian hematopoietic system has evolved multiple conserved requirements for Slicer-dependent miRNA biogenesis.

KEYWORDS:

Ago2; Argonaute; RNAi; Slicer; erythropoiesis; hematopoietic; miR-451; miR-486; miRNA; microRNA

PMID:
29351846
PMCID:
PMC5824974
[Available on 2019-01-18]
DOI:
10.1016/j.molcel.2017.12.027

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