1. Chromosomes and Gene Expression
  2. Genetics and Genomics
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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation

  1. Daniel R Fuentes
  2. Tomek Swigut
  3. Joanna Wysocka  Is a corresponding author
  1. Stanford University School of Medicine, United States
Research Article
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Cite as: eLife 2018;7:e35989 doi: 10.7554/eLife.35989

Abstract

Recent work suggests extensive adaptation of transposable elements (TEs) for host gene regulation. However, high numbers of integrations typical of TEs, coupled with sequence divergence within families, have made systematic interrogation of the regulatory contributions of TEs challenging. Here, we employ CARGO, our recent method for CRISPR gRNA multiplexing, to facilitate targeting of LTR5HS, an ape-specific class of HERVK (HML-2) LTRs that is active during early development and present in ~700 copies throughout the human genome. We combine CARGO with CRISPR activation or interference to, respectively, induce or silence LTR5HS en masse, and demonstrate that this system robustly targets the vast majority of LTR5HS insertions. Remarkably, activation/silencing of LTR5HS is associated with reciprocal up- and down-regulation of hundreds of human genes. These effects require presence of retroviral sequences, but occur over long genomic distances, consistent with a pervasive function of LTR5HS elements as early embryonic enhancers in apes.

Article and author information

Author details

  1. Daniel R Fuentes

    Cancer Biology Program, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-0412-6933
  2. Tomek Swigut

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-7649-6781
  3. Joanna Wysocka

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    For correspondence
    wysocka@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-6909-6544

Funding

National Science Foundation (Graduate Research Fellowship Program)

  • Daniel R Fuentes

Howard Hughes Medical Institute

  • Joanna Wysocka

National Institute of General Medical Sciences (R01GM112720)

  • Joanna Wysocka

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edith Heard, Institut Curie, France

Publication history

  1. Received: February 26, 2018
  2. Accepted: August 1, 2018
  3. Accepted Manuscript published: August 2, 2018 (version 1)

Copyright

© 2018, Fuentes 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.

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