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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation
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 e...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158008/ https://www.ncbi.nlm.nih.gov/pubmed/30070637 http://dx.doi.org/10.7554/eLife.35989 |
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author | Fuentes, Daniel R Swigut, Tomek Wysocka, Joanna |
author_facet | Fuentes, Daniel R Swigut, Tomek Wysocka, Joanna |
author_sort | Fuentes, Daniel R |
collection | PubMed |
description | 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 the presence of retroviral sequences, but occur over long genomic distances, consistent with a pervasive function of LTR5HS elements as early embryonic enhancers in apes. |
format | Online Article Text |
id | pubmed-6158008 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-61580082018-09-27 Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation Fuentes, Daniel R Swigut, Tomek Wysocka, Joanna eLife Chromosomes and Gene Expression 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 the presence of retroviral sequences, but occur over long genomic distances, consistent with a pervasive function of LTR5HS elements as early embryonic enhancers in apes. eLife Sciences Publications, Ltd 2018-08-02 /pmc/articles/PMC6158008/ /pubmed/30070637 http://dx.doi.org/10.7554/eLife.35989 Text en © 2018, Fuentes et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Chromosomes and Gene Expression Fuentes, Daniel R Swigut, Tomek Wysocka, Joanna Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation |
title | Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation |
title_full | Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation |
title_fullStr | Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation |
title_full_unstemmed | Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation |
title_short | Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation |
title_sort | systematic perturbation of retroviral ltrs reveals widespread long-range effects on human gene regulation |
topic | Chromosomes and Gene Expression |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158008/ https://www.ncbi.nlm.nih.gov/pubmed/30070637 http://dx.doi.org/10.7554/eLife.35989 |
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