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Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in...

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Autores principales: Barnada, Samantha M., Isopi, Andrew, Tejada-Martinez, Daniela, Goubert, Clément, Patoori, Sruti, Pagliaroli, Luca, Tracewell, Mason, Trizzino, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239442/
https://www.ncbi.nlm.nih.gov/pubmed/35704668
http://dx.doi.org/10.1371/journal.pgen.1010225
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author Barnada, Samantha M.
Isopi, Andrew
Tejada-Martinez, Daniela
Goubert, Clément
Patoori, Sruti
Pagliaroli, Luca
Tracewell, Mason
Trizzino, Marco
author_facet Barnada, Samantha M.
Isopi, Andrew
Tejada-Martinez, Daniela
Goubert, Clément
Patoori, Sruti
Pagliaroli, Luca
Tracewell, Mason
Trizzino, Marco
author_sort Barnada, Samantha M.
collection PubMed
description Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that ~750 SVAs are co-opted as functional cis-regulatory elements in human induced pluripotent stem cells. These SVAs are significantly closer to genes and harbor more transcription factor binding sites than non-co-opted SVAs. We show that a long DNA motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs and that these two transcription factors bind consecutively on the TE sequence. We used CRISPRi to epigenetically repress active SVAs in stem cell-like NCCIT cells. Epigenetic perturbation of active SVAs strongly attenuated YY1/OCT4 binding and influenced neighboring gene expression. Ultimately, SVA repression resulted in ~3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs modulate human gene expression, and uncovered that location and sequence composition contribute to SVA domestication into gene regulatory networks.
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spelling pubmed-92394422022-06-29 Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells Barnada, Samantha M. Isopi, Andrew Tejada-Martinez, Daniela Goubert, Clément Patoori, Sruti Pagliaroli, Luca Tracewell, Mason Trizzino, Marco PLoS Genet Research Article Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that ~750 SVAs are co-opted as functional cis-regulatory elements in human induced pluripotent stem cells. These SVAs are significantly closer to genes and harbor more transcription factor binding sites than non-co-opted SVAs. We show that a long DNA motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs and that these two transcription factors bind consecutively on the TE sequence. We used CRISPRi to epigenetically repress active SVAs in stem cell-like NCCIT cells. Epigenetic perturbation of active SVAs strongly attenuated YY1/OCT4 binding and influenced neighboring gene expression. Ultimately, SVA repression resulted in ~3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs modulate human gene expression, and uncovered that location and sequence composition contribute to SVA domestication into gene regulatory networks. Public Library of Science 2022-06-15 /pmc/articles/PMC9239442/ /pubmed/35704668 http://dx.doi.org/10.1371/journal.pgen.1010225 Text en © 2022 Barnada et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Barnada, Samantha M.
Isopi, Andrew
Tejada-Martinez, Daniela
Goubert, Clément
Patoori, Sruti
Pagliaroli, Luca
Tracewell, Mason
Trizzino, Marco
Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells
title Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells
title_full Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells
title_fullStr Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells
title_full_unstemmed Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells
title_short Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells
title_sort genomic features underlie the co-option of sva transposons as cis-regulatory elements in human pluripotent stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239442/
https://www.ncbi.nlm.nih.gov/pubmed/35704668
http://dx.doi.org/10.1371/journal.pgen.1010225
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