1. Chromosomes and Gene Expression
Download icon

Genomic DNA transposition induced by human PGBD5

  1. Anton G Henssen
  2. Elizabeth Henaff
  3. Eileen Jiang
  4. Amy R Eisenberg
  5. Julianne R Carson
  6. Camila M Villasante
  7. Mondira Ray
  8. Eric Still
  9. Melissa Burns
  10. Jorge Gandara
  11. Cedric Feschotte
  12. Christopher E Mason
  13. Alex Kentsis  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. Weill Cornell Medical College, United States
  3. Harvard Medical School, United States
  4. University of Utah School of Medicine, United States
Research Article
  • Cited 31
  • Views 5,522
  • Annotations
Cite this article as: eLife 2015;4:e10565 doi: 10.7554/eLife.10565

Abstract

Transposons are mobile genetic elements that are found in nearly all organisms, including humans. Mobilization of DNA transposons by transposase enzymes can cause genomic rearrangements, but our knowledge of human genes derived from transposases is limited. Here, we find that the protein encoded by human PGBD5, the most evolutionarily conserved transposable element-derived gene in vertebrates, can induce stereotypical cut-and-paste DNA transposition in human cells. Genomic integration activity of PGBD5 requires distinct aspartic acid residues in its transposase domain, and specific DNA sequences containing inverted terminal repeats with similarity to piggyBac transposons. DNA transposition catalyzed by PGBD5 in human cells occurs genome-wide, with precise transposon excision and preference for insertion at TTAA sites. The apparent conservation of DNA transposition activity by PGBD5 suggests that genomic remodeling contributes to its biological function.

Article and author information

Author details

  1. Anton G Henssen

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Elizabeth Henaff

    Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Eileen Jiang

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amy R Eisenberg

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Julianne R Carson

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Camila M Villasante

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Mondira Ray

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Eric Still

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Melissa Burns

    Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jorge Gandara

    Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Cedric Feschotte

    Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Christopher E Mason

    Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Alex Kentsis

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    kentsisresearchgroup@gmail.com
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Michael R Botchan, University of California, Berkeley, United States

Publication history

  1. Received: August 3, 2015
  2. Accepted: September 23, 2015
  3. Accepted Manuscript published: September 25, 2015 (version 1)
  4. Version of Record published: October 29, 2015 (version 2)

Copyright

© 2015, Henssen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,522
    Page views
  • 870
    Downloads
  • 31
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Anthony S Findley et al.
    Research Article

    Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

    1. Cancer Biology
    2. Chromosomes and Gene Expression
    Shou Liu et al.
    Research Article

    ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of Arid1a deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species (ROS). As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.