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Nat Genet. 2015 Jul;47(7):766-75. doi: 10.1038/ng.3321. Epub 2015 Jun 1.

An allelic series of miR-17 ∼ 92-mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron.

Author information

1
1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Oncology Research Unit, Pfizer, Inc., Pearl River, New York, USA.
2
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Weill Cornell Graduate School of Medical Sciences of Cornell University, New York, New York, USA.
4
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
1] Human Oncology and Pathogenesis Program. Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA.
7
1] Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. [2] Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.

Abstract

Polycistronic microRNA (miRNA) clusters are a common feature of vertebrate genomes. The coordinated expression of miRNAs belonging to different seed families from a single transcriptional unit suggests functional cooperation, but this hypothesis has not been experimentally tested. Here we report the characterization of an allelic series of genetically engineered mice harboring selective targeted deletions of individual components of the miR-17 ∼ 92 cluster. Our results demonstrate the coexistence of functional cooperation and specialization among members of this cluster, identify a previously undescribed function for the miR-17 seed family in controlling axial patterning in vertebrates and show that loss of miR-19 selectively impairs Myc-driven tumorigenesis in two models of human cancer. By integrating phenotypic analysis and gene expression profiling, we provide a genome-wide view of how the components of a polycistronic miRNA cluster affect gene expression in vivo. The reagents and data sets reported here will accelerate exploration of the complex biological functions of this important miRNA cluster.

PMID:
26029871
PMCID:
PMC4485521
DOI:
10.1038/ng.3321
[Indexed for MEDLINE]
Free PMC Article

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