Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation
- Stanford University School of Medicine, United States
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.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE111331, GSE111332 and GSE111337.
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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation [ChIP-seq]ublicly available at the NCBI Gene Expression Omnibus (accession no: GSE111331).
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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation [RNA-seq]Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE111332).
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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation [RNA-seq]Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE111337).
Article and author information
Author details
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
- Edith Heard, Institut Curie, France
Version history
- Received: February 26, 2018
- Accepted: August 1, 2018
- Accepted Manuscript published: August 2, 2018 (version 1)
- Version of Record published: September 26, 2018 (version 2)
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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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation
eLife 7:e35989.
https://doi.org/10.7554/eLife.35989
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