Sleeping Beauty transposon insertional mutagenesis based mouse models for cancer gene discovery

doi:10.1016/j.gde.2015.04.007

Review

. 2015 Feb:30:66-72.

doi: 10.1016/j.gde.2015.04.007. Epub 2015 Jun 4.

Sleeping Beauty transposon insertional mutagenesis based mouse models for cancer gene discovery

Branden S Moriarity¹, David A Largaespada²

Affiliations

¹ Department of Pediatrics, University of Minnesota Minneapolis, MN 55455, United States; Center for Genome Engineering, University of Minnesota Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota Minneapolis, MN 55455, United States.
² Department of Pediatrics, University of Minnesota Minneapolis, MN 55455, United States; Center for Genome Engineering, University of Minnesota Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota Minneapolis, MN 55455, United States; Department of Genetics, Cell Biology, and Development, University of Minnesota Minneapolis, MN 55455, United States. Electronic address: larga002@umn.edu.

PMID: 26051241
PMCID: PMC4900178
DOI: 10.1016/j.gde.2015.04.007

Review

Sleeping Beauty transposon insertional mutagenesis based mouse models for cancer gene discovery

Branden S Moriarity et al. Curr Opin Genet Dev. 2015 Feb.

. 2015 Feb:30:66-72.

doi: 10.1016/j.gde.2015.04.007. Epub 2015 Jun 4.

Authors

Branden S Moriarity¹, David A Largaespada²

Affiliations

¹ Department of Pediatrics, University of Minnesota Minneapolis, MN 55455, United States; Center for Genome Engineering, University of Minnesota Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota Minneapolis, MN 55455, United States.
² Department of Pediatrics, University of Minnesota Minneapolis, MN 55455, United States; Center for Genome Engineering, University of Minnesota Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota Minneapolis, MN 55455, United States; Department of Genetics, Cell Biology, and Development, University of Minnesota Minneapolis, MN 55455, United States. Electronic address: larga002@umn.edu.

PMID: 26051241
PMCID: PMC4900178
DOI: 10.1016/j.gde.2015.04.007

Abstract

Large-scale genomic efforts to study human cancer, such as the cancer gene atlas (TCGA), have identified numerous cancer drivers in a wide variety of tumor types. However, there are limitations to this approach, the mutations and expression or copy number changes that are identified are not always clearly functionally relevant, and only annotated genes and genetic elements are thoroughly queried. The use of complimentary, nonbiased, functional approaches to identify drivers of cancer development and progression is ideal to maximize the rate at which cancer discoveries are achieved. One such approach that has been successful is the use of the Sleeping Beauty (SB) transposon-based mutagenesis system in mice. This system uses a conditionally expressed transposase and mutagenic transposon allele to _target mutagenesis to somatic cells of a given tissue in mice to cause random mutations leading to tumor development. Analysis of tumors for transposon common insertion sites (CIS) identifies candidate cancer genes specific to that tumor type. While similar screens have been performed in mice with the PiggyBac (PB) transposon and viral approaches, we limit extensive discussion to SB. Here we discuss the basic structure of these screens, screens that have been performed, methods used to identify CIS.

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Figures

**Figure 1**
Basic structure of a SB cancer screen. Most screens to date utilize mice carrying the conditional SB11 *Rosa26* “knockin” allele (*Rosa26-LSL-SB11*) and T2/Onc concatemer, which are crossed to mice carrying a tissue specific Cre transgene (TSP-Cre) and in many cases some cancer predisposing mutation (e.g. *LSL-Trp53^R270H*). Important choices to be made at each step of such a screen are boxed.

**Figure 2**
Potential future refinements to SB cancer screens. Improvements and refinements to *in vivo* cancer screening using SB might be made at the level of the mouse, analysis of the primary tumor, or single cells isolated from the primary tumor.

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References

1. Ivics Z, Hackett PB, Plasterk RH, Izsvak Z. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell. 1997;91:501–510. This paper describes the molecular reconstruction of SB for the first time and is the landmark paper in this field.
1. Cui Z, Geurts AM, Liu G, Kaufman CD, Hackett PB. Structure-function analysis of the inverted terminal repeats of the sleeping beauty transposon. J Mol Biol. 2002;318:1221–1235. - PubMed
1. Geurts AM, Yang Y, Clark KJ, Liu G, Cui Z, Dupuy AJ, Bell JB, Largaespada DA, Hackett PB. Gene transfer into genomes of human cells by the sleeping beauty transposon system. Mol Ther. 2003;8:108–117. - PubMed
1. Mates L, Chuah MK, Belay E, Jerchow B, Manoj N, Acosta-Sanchez A, Grzela DP, Schmitt A, Becker K, Matrai J, et al. Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates. Nat Genet. 2009;41:753–761. - PubMed
1. Horie K, Kuroiwa A, Ikawa M, Okabe M, Kondoh G, Matsuda Y, Takeda J. Efficient chromosomal transposition of a Tc1/mariner- like transposon Sleeping Beauty in mice. Proc Natl Acad Sci U S A. 2001;98:9191–9196. - PMC - PubMed

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[1] Ivics Z, Hackett PB, Plasterk RH, Izsvak Z. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell. 1997;91:501–510. This paper describes the molecular reconstruction of SB for the first time and is the landmark paper in this field.

[2] Ivics Z, Hackett PB, Plasterk RH, Izsvak Z. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell. 1997;91:501–510. This paper describes the molecular reconstruction of SB for the first time and is the landmark paper in this field.

[3] Cui Z, Geurts AM, Liu G, Kaufman CD, Hackett PB. Structure-function analysis of the inverted terminal repeats of the sleeping beauty transposon. J Mol Biol. 2002;318:1221–1235. - PubMed

[4] Cui Z, Geurts AM, Liu G, Kaufman CD, Hackett PB. Structure-function analysis of the inverted terminal repeats of the sleeping beauty transposon. J Mol Biol. 2002;318:1221–1235. - PubMed

[5] Geurts AM, Yang Y, Clark KJ, Liu G, Cui Z, Dupuy AJ, Bell JB, Largaespada DA, Hackett PB. Gene transfer into genomes of human cells by the sleeping beauty transposon system. Mol Ther. 2003;8:108–117. - PubMed

[6] Geurts AM, Yang Y, Clark KJ, Liu G, Cui Z, Dupuy AJ, Bell JB, Largaespada DA, Hackett PB. Gene transfer into genomes of human cells by the sleeping beauty transposon system. Mol Ther. 2003;8:108–117. - PubMed

[7] Mates L, Chuah MK, Belay E, Jerchow B, Manoj N, Acosta-Sanchez A, Grzela DP, Schmitt A, Becker K, Matrai J, et al. Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates. Nat Genet. 2009;41:753–761. - PubMed

[8] Mates L, Chuah MK, Belay E, Jerchow B, Manoj N, Acosta-Sanchez A, Grzela DP, Schmitt A, Becker K, Matrai J, et al. Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates. Nat Genet. 2009;41:753–761. - PubMed

[9] Horie K, Kuroiwa A, Ikawa M, Okabe M, Kondoh G, Matsuda Y, Takeda J. Efficient chromosomal transposition of a Tc1/mariner- like transposon Sleeping Beauty in mice. Proc Natl Acad Sci U S A. 2001;98:9191–9196. - PMC - PubMed

[10] Horie K, Kuroiwa A, Ikawa M, Okabe M, Kondoh G, Matsuda Y, Takeda J. Efficient chromosomal transposition of a Tc1/mariner- like transposon Sleeping Beauty in mice. Proc Natl Acad Sci U S A. 2001;98:9191–9196. - PMC - PubMed

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Sleeping Beauty transposon insertional mutagenesis based mouse models for cancer gene discovery

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Sleeping Beauty transposon insertional mutagenesis based mouse models for cancer gene discovery

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