Transposon Mutagenesis

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Michael B. Mann - One of the best experts on this subject based on the ideXlab platform.

  • Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation
    Cancers, 2021
    Co-Authors: Aziz Aiderus, Jerrold M. Ward, Justin Y. Newberg, Neal G. Copeland, Nancy A. Jenkins, Ana M. Contreras-sandoval, Amanda L. Meshey, Deborah A. Swing, Karen M. Mann, Michael B. Mann
    Abstract:

    A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty Transposon Mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body Transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

  • Transposon Mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression
    Proceedings of the National Academy of Sciences of the United States of America, 2016
    Co-Authors: Roberto Rangel, Michael B. Mann, Justin Y. Newberg, Song Choon Lee, Kenneth H K Ban, Liliana Guzman-rojas, Takahiro Kodama, Leslie A. Mcnoe, Luxmanan Selvanesan, Jerrold M. Ward
    Abstract:

    Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a Transposon Mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon Mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

  • Transposon Mutagenesis identifies genetic drivers of Braf^V600E melanoma
    Nature Genetics, 2015
    Co-Authors: Michael B. Mann, Michael A. Black, Devin J. Jones, Jerrold M. Ward, Christopher Chin Kuan Yew, Justin Y. Newberg, Adam J. Dupuy, Alistair G. Rust, Marcus Bosenberg, Martin Mcmahon
    Abstract:

    Nancy Jenkins, Neal Copeland and colleagues report the results of a Sleeping Beauty Transposon Mutagenesis screen in mice carrying a melanocyte-specific inducible Braf ^V600E allele. Analysis of Transposon insertion sites identified candidate genetic drivers of melanoma. Although nearly half of human melanomas harbor oncogenic BRAF ^V600E mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) Transposon-mediated Mutagenesis drives melanoma progression in Braf ^V600E mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB Mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF ^V600E melanoma and discover new genes with potential clinical importance in human melanoma.

  • Transposon Mutagenesis identifies genetic drivers of Braf V600E melanoma
    Nature genetics, 2015
    Co-Authors: Michael B. Mann, Michael A. Black, Devin J. Jones, Jerrold M. Ward, Christopher Chin Kuan Yew, Justin Y. Newberg, Adam J. Dupuy, Alistair G. Rust, Marcus Bosenberg, Martin Mcmahon
    Abstract:

    Nancy Jenkins, Neal Copeland and colleagues report the results of a Sleeping Beauty Transposon Mutagenesis screen in mice carrying a melanocyte-specific inducible BrafV600E allele. Analysis of Transposon insertion sites identified candidate genetic drivers of melanoma.

  • Transposon Mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression
    Nature Genetics, 2015
    Co-Authors: Haruna Takeda, Michael B. Mann, Jerrold M. Ward, Christopher Chin Kuan Yew, Alistair G. Rust, Zhubo Wei, Neal G. Copeland, Hideto Koso, David J Adams, Nancy A. Jenkins
    Abstract:

    To provide a more comprehensive understanding of the genes and evolutionary forces driving colorectal cancer (CRC) progression, we performed Sleeping Beauty (SB) Transposon Mutagenesis screens in mice carrying sensitizing mutations in genes that act at different stages of tumor progression. This approach allowed us to identify a set of genes that appear to be highly relevant for CRC and to provide a better understanding of the evolutionary forces and systems properties of CRC. We also identified six genes driving malignant tumor progression and a new human CRC tumor-suppressor gene, ZNF292, that might also function in other types of cancer. Our comprehensive CRC data set provides a resource with which to develop new therapies for treating CRC.

J.mark Weber - One of the best experts on this subject based on the ideXlab platform.

  • Application of In Vitro Transposon Mutagenesis to Erythromycin Strain Improvement in Saccharopolyspora erythraea.
    Methods in molecular biology (Clifton N.J.), 2016
    Co-Authors: J.mark Weber, William H. Cernota, Andrew Reeves, Roy K. Wesley
    Abstract:

    Transposon Mutagenesis is an invaluable technique in molecular biology for the creation of random mutations that can be easily identified and mapped. However, in the field of microbial strain improvement, Transposon Mutagenesis has scarcely been used; instead, chemical and physical mutagenic methods have been traditionally favored. Transposons have the advantage of creating single mutations in the genome, making phenotype to genotype assignments less challenging than with traditional mutagens which commonly create multiple mutations in the genome. The site of a Transposon mutation can also be readily mapped using DNA sequencing primer sites engineered into the Transposon termini. In this chapter an in vitro method for Transposon Mutagenesis of Saccharopolyspora erythraea is presented. Since in vivo Transposon tools are not available for most actinomycetes including S. erythraea, an in vitro method was developed. The in vitro method involves a significant investment in time and effort to create the mutants, but once the mutants are made and screened, a large number of highly relevant mutations of direct interest to erythromycin production can be found.

  • Random Transposon Mutagenesis of the Saccharopolyspora erythraea genome reveals additional genes influencing erythromycin biosynthesis.
    FEMS microbiology letters, 2015
    Co-Authors: Andrij Fedashchin, William H. Cernota, Melissa C. Gonzalez, Benjamin I. Leach, Noelle Kwan, Roy K. Wesley, J.mark Weber
    Abstract:

    A single cycle of strain improvement was performed in Saccharopolyspora erythraea mutB and 15 genotypes influencing erythromycin production were found. Genotypes generated by Transposon Mutagenesis appeared in the screen at a frequency of ∼3%. Mutations affecting central metabolism and regulatory genes were found, as well as hydrolases, peptidases, glycosyl transferases and unknown genes. Only one mutant retained high erythromycin production when scaled-up from micro-agar plug fermentations to shake flasks. This mutant had a knockout of the cwh1 gene (SACE_1598), encoding a cell-wall-associated hydrolase. The cwh1 knockout produced visible growth and morphological defects on solid medium. This study demonstrated that random Transposon Mutagenesis uncovers strain improvement-related genes potentially useful for strain engineering.

  • Metabolic Engineering of Antibiotic-Producing Actinomycetes Using In Vitro Transposon Mutagenesis
    Methods in molecular biology (Clifton N.J.), 2011
    Co-Authors: Andrew Reeves, J.mark Weber
    Abstract:

    A program of mutation and screening, with stepwise reverse engineering or "decoding" of the improved strain, is a way to better understand the genetics and physiology of the strain improvement process. As more is learned about the genetics of strain improvement, it is hoped that more fundamental principles will emerge about the types of mutations and genetic manipulations that reliably lead to higher producing strains. This will accelerate the construction of higher producing strains by metabolic engineering in the future. In this chapter, a detailed tagged Mutagenesis approach is described using in vitro Transposon Mutagenesis which allowed the successful identification of key genes involved in macrolide (erythromycin) antibiotic biosynthesis.

Nancy A. Jenkins - One of the best experts on this subject based on the ideXlab platform.

  • Identification of cancer driver genes using Sleeping Beauty Transposon Mutagenesis.
    Cancer science, 2021
    Co-Authors: Haruna Takeda, Nancy A. Jenkins, Neal G. Copeland
    Abstract:

    Cancer genome sequencing studies have identified driver genes for a variety of different cancers and helped to understand the genetic landscape of human cancer. It is still challenging, however, to identify cancer driver genes with confidence simply from genetic data alone. In vivo forward genetic screens using Sleeping Beauty (SB) Transposon Mutagenesis provides another powerful genetic tool for identifying candidate cancer driver genes in wild type and sensitized mouse tumors. By comparing cancer driver genes identified in human and mouse tumors, cancer driver genes can be identified with additional confidence based upon comparative oncogenomics. This review describes how SB Mutagenesis works in mice and focuses on studies that have identified cancer driver genes in the mouse gastrointestinal tract.

  • Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation
    Cancers, 2021
    Co-Authors: Aziz Aiderus, Jerrold M. Ward, Justin Y. Newberg, Neal G. Copeland, Nancy A. Jenkins, Ana M. Contreras-sandoval, Amanda L. Meshey, Deborah A. Swing, Karen M. Mann, Michael B. Mann
    Abstract:

    A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty Transposon Mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body Transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

  • Abstract 3932: Using Sleeping Beauty Transposon Mutagenesis to identify CRC driver genes
    Molecular and Cellular Biology, 2015
    Co-Authors: Zhubo Wei, Haruna Takeda, Neal G. Copeland, Nancy A. Jenkins
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA In order to better understand the initiation and development of colorectal cancer (CRC), Sleeping Beauty (SB) Transposon Mutagenesis screens were performed in mice with mutations in genes that play important roles in differen stages of CRC. Functional validation assays, including invasion assay and xenograft assay, were carried out for the candidate genes that were selected by their potentials in tumor progression and/or human CRC. We identified six genes driving malignant tumor progression, and a new human CRC tumor suppressor gene, ZNF292, that may also function in other types of cancer. More detailed investigations are being done for those identified genes, including experiments using knockout mice. Our study provides a resource for the development of new CRC therapies. Citation Format: Zhubo Wei, Haruna Takeda, Neal G. Copeland, Nancy A. Jenkins. Using Sleeping Beauty Transposon Mutagenesis to identify CRC driver genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3932. doi:10.1158/1538-7445.AM2015-3932

  • Transposon Mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression
    Nature Genetics, 2015
    Co-Authors: Haruna Takeda, Michael B. Mann, Jerrold M. Ward, Christopher Chin Kuan Yew, Alistair G. Rust, Zhubo Wei, Neal G. Copeland, Hideto Koso, David J Adams, Nancy A. Jenkins
    Abstract:

    To provide a more comprehensive understanding of the genes and evolutionary forces driving colorectal cancer (CRC) progression, we performed Sleeping Beauty (SB) Transposon Mutagenesis screens in mice carrying sensitizing mutations in genes that act at different stages of tumor progression. This approach allowed us to identify a set of genes that appear to be highly relevant for CRC and to provide a better understanding of the evolutionary forces and systems properties of CRC. We also identified six genes driving malignant tumor progression and a new human CRC tumor-suppressor gene, ZNF292, that might also function in other types of cancer. Our comprehensive CRC data set provides a resource with which to develop new therapies for treating CRC.

Neal G. Copeland - One of the best experts on this subject based on the ideXlab platform.

  • Identification of cancer driver genes using Sleeping Beauty Transposon Mutagenesis.
    Cancer science, 2021
    Co-Authors: Haruna Takeda, Nancy A. Jenkins, Neal G. Copeland
    Abstract:

    Cancer genome sequencing studies have identified driver genes for a variety of different cancers and helped to understand the genetic landscape of human cancer. It is still challenging, however, to identify cancer driver genes with confidence simply from genetic data alone. In vivo forward genetic screens using Sleeping Beauty (SB) Transposon Mutagenesis provides another powerful genetic tool for identifying candidate cancer driver genes in wild type and sensitized mouse tumors. By comparing cancer driver genes identified in human and mouse tumors, cancer driver genes can be identified with additional confidence based upon comparative oncogenomics. This review describes how SB Mutagenesis works in mice and focuses on studies that have identified cancer driver genes in the mouse gastrointestinal tract.

  • Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation
    Cancers, 2021
    Co-Authors: Aziz Aiderus, Jerrold M. Ward, Justin Y. Newberg, Neal G. Copeland, Nancy A. Jenkins, Ana M. Contreras-sandoval, Amanda L. Meshey, Deborah A. Swing, Karen M. Mann, Michael B. Mann
    Abstract:

    A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty Transposon Mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body Transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

  • Abstract 3932: Using Sleeping Beauty Transposon Mutagenesis to identify CRC driver genes
    Molecular and Cellular Biology, 2015
    Co-Authors: Zhubo Wei, Haruna Takeda, Neal G. Copeland, Nancy A. Jenkins
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA In order to better understand the initiation and development of colorectal cancer (CRC), Sleeping Beauty (SB) Transposon Mutagenesis screens were performed in mice with mutations in genes that play important roles in differen stages of CRC. Functional validation assays, including invasion assay and xenograft assay, were carried out for the candidate genes that were selected by their potentials in tumor progression and/or human CRC. We identified six genes driving malignant tumor progression, and a new human CRC tumor suppressor gene, ZNF292, that may also function in other types of cancer. More detailed investigations are being done for those identified genes, including experiments using knockout mice. Our study provides a resource for the development of new CRC therapies. Citation Format: Zhubo Wei, Haruna Takeda, Neal G. Copeland, Nancy A. Jenkins. Using Sleeping Beauty Transposon Mutagenesis to identify CRC driver genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3932. doi:10.1158/1538-7445.AM2015-3932

  • Transposon Mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression
    Nature Genetics, 2015
    Co-Authors: Haruna Takeda, Michael B. Mann, Jerrold M. Ward, Christopher Chin Kuan Yew, Alistair G. Rust, Zhubo Wei, Neal G. Copeland, Hideto Koso, David J Adams, Nancy A. Jenkins
    Abstract:

    To provide a more comprehensive understanding of the genes and evolutionary forces driving colorectal cancer (CRC) progression, we performed Sleeping Beauty (SB) Transposon Mutagenesis screens in mice carrying sensitizing mutations in genes that act at different stages of tumor progression. This approach allowed us to identify a set of genes that appear to be highly relevant for CRC and to provide a better understanding of the evolutionary forces and systems properties of CRC. We also identified six genes driving malignant tumor progression and a new human CRC tumor-suppressor gene, ZNF292, that might also function in other types of cancer. Our comprehensive CRC data set provides a resource with which to develop new therapies for treating CRC.

Jerrold M. Ward - One of the best experts on this subject based on the ideXlab platform.

  • Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation
    Cancers, 2021
    Co-Authors: Aziz Aiderus, Jerrold M. Ward, Justin Y. Newberg, Neal G. Copeland, Nancy A. Jenkins, Ana M. Contreras-sandoval, Amanda L. Meshey, Deborah A. Swing, Karen M. Mann, Michael B. Mann
    Abstract:

    A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty Transposon Mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body Transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

  • Transposon Mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression
    Proceedings of the National Academy of Sciences of the United States of America, 2016
    Co-Authors: Roberto Rangel, Michael B. Mann, Justin Y. Newberg, Song Choon Lee, Kenneth H K Ban, Liliana Guzman-rojas, Takahiro Kodama, Leslie A. Mcnoe, Luxmanan Selvanesan, Jerrold M. Ward
    Abstract:

    Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a Transposon Mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon Mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

  • Transposon Mutagenesis identifies genetic drivers of Braf^V600E melanoma
    Nature Genetics, 2015
    Co-Authors: Michael B. Mann, Michael A. Black, Devin J. Jones, Jerrold M. Ward, Christopher Chin Kuan Yew, Justin Y. Newberg, Adam J. Dupuy, Alistair G. Rust, Marcus Bosenberg, Martin Mcmahon
    Abstract:

    Nancy Jenkins, Neal Copeland and colleagues report the results of a Sleeping Beauty Transposon Mutagenesis screen in mice carrying a melanocyte-specific inducible Braf ^V600E allele. Analysis of Transposon insertion sites identified candidate genetic drivers of melanoma. Although nearly half of human melanomas harbor oncogenic BRAF ^V600E mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) Transposon-mediated Mutagenesis drives melanoma progression in Braf ^V600E mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB Mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF ^V600E melanoma and discover new genes with potential clinical importance in human melanoma.

  • Transposon Mutagenesis identifies genetic drivers of Braf V600E melanoma
    Nature genetics, 2015
    Co-Authors: Michael B. Mann, Michael A. Black, Devin J. Jones, Jerrold M. Ward, Christopher Chin Kuan Yew, Justin Y. Newberg, Adam J. Dupuy, Alistair G. Rust, Marcus Bosenberg, Martin Mcmahon
    Abstract:

    Nancy Jenkins, Neal Copeland and colleagues report the results of a Sleeping Beauty Transposon Mutagenesis screen in mice carrying a melanocyte-specific inducible BrafV600E allele. Analysis of Transposon insertion sites identified candidate genetic drivers of melanoma.

  • Transposon Mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression
    Nature Genetics, 2015
    Co-Authors: Haruna Takeda, Michael B. Mann, Jerrold M. Ward, Christopher Chin Kuan Yew, Alistair G. Rust, Zhubo Wei, Neal G. Copeland, Hideto Koso, David J Adams, Nancy A. Jenkins
    Abstract:

    To provide a more comprehensive understanding of the genes and evolutionary forces driving colorectal cancer (CRC) progression, we performed Sleeping Beauty (SB) Transposon Mutagenesis screens in mice carrying sensitizing mutations in genes that act at different stages of tumor progression. This approach allowed us to identify a set of genes that appear to be highly relevant for CRC and to provide a better understanding of the evolutionary forces and systems properties of CRC. We also identified six genes driving malignant tumor progression and a new human CRC tumor-suppressor gene, ZNF292, that might also function in other types of cancer. Our comprehensive CRC data set provides a resource with which to develop new therapies for treating CRC.

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