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Statistical learning quantifies transposable element-mediated cis-regulation

BACKGROUND: Transposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryogenesis to innate immune responses. Because of their repetitive...

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Autores principales: Pulver, Cyril, Grun, Delphine, Duc, Julien, Sheppard, Shaoline, Planet, Evarist, Coudray, Alexandre, de Fondeville, Raphaël, Pontis, Julien, Trono, Didier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637000/
https://www.ncbi.nlm.nih.gov/pubmed/37950299
http://dx.doi.org/10.1186/s13059-023-03085-7
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author Pulver, Cyril
Grun, Delphine
Duc, Julien
Sheppard, Shaoline
Planet, Evarist
Coudray, Alexandre
de Fondeville, Raphaël
Pontis, Julien
Trono, Didier
author_facet Pulver, Cyril
Grun, Delphine
Duc, Julien
Sheppard, Shaoline
Planet, Evarist
Coudray, Alexandre
de Fondeville, Raphaël
Pontis, Julien
Trono, Didier
author_sort Pulver, Cyril
collection PubMed
description BACKGROUND: Transposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryogenesis to innate immune responses. Because of their repetitive nature, TEs have the potential to form CRE platforms enabling the coordinated and genome-wide regulation of protein-coding genes by only a handful of trans-acting transcription factors (TFs). RESULTS: Here, we directly test this hypothesis through mathematical modeling and demonstrate that differences in expression at protein-coding genes alone are sufficient to estimate the magnitude and significance of TE-contributed cis-regulatory activities, even in contexts where TE-derived transcription fails to do so. We leverage hundreds of overexpression experiments and estimate that, overall, gene expression is influenced by TE-embedded CREs situated within approximately 500 kb of promoters. Focusing on the cis-regulatory potential of TEs within the gene regulatory network of human embryonic stem cells, we find that pluripotency-specific and evolutionarily young TE subfamilies can be reactivated by TFs involved in post-implantation embryogenesis. Finally, we show that TE subfamilies can be split into truly regulatorily active versus inactive fractions based on additional information such as matched epigenomic data, observing that TF binding may better predict TE cis-regulatory activity than differences in histone marks. CONCLUSION: Our results suggest that TE-embedded CREs contribute to gene regulation during and beyond gastrulation. On a methodological level, we provide a statistical tool that infers TE-dependent cis-regulation from RNA-seq data alone, thus facilitating the study of TEs in the next-generation sequencing era. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-03085-7.
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spelling pubmed-106370002023-11-11 Statistical learning quantifies transposable element-mediated cis-regulation Pulver, Cyril Grun, Delphine Duc, Julien Sheppard, Shaoline Planet, Evarist Coudray, Alexandre de Fondeville, Raphaël Pontis, Julien Trono, Didier Genome Biol Research BACKGROUND: Transposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryogenesis to innate immune responses. Because of their repetitive nature, TEs have the potential to form CRE platforms enabling the coordinated and genome-wide regulation of protein-coding genes by only a handful of trans-acting transcription factors (TFs). RESULTS: Here, we directly test this hypothesis through mathematical modeling and demonstrate that differences in expression at protein-coding genes alone are sufficient to estimate the magnitude and significance of TE-contributed cis-regulatory activities, even in contexts where TE-derived transcription fails to do so. We leverage hundreds of overexpression experiments and estimate that, overall, gene expression is influenced by TE-embedded CREs situated within approximately 500 kb of promoters. Focusing on the cis-regulatory potential of TEs within the gene regulatory network of human embryonic stem cells, we find that pluripotency-specific and evolutionarily young TE subfamilies can be reactivated by TFs involved in post-implantation embryogenesis. Finally, we show that TE subfamilies can be split into truly regulatorily active versus inactive fractions based on additional information such as matched epigenomic data, observing that TF binding may better predict TE cis-regulatory activity than differences in histone marks. CONCLUSION: Our results suggest that TE-embedded CREs contribute to gene regulation during and beyond gastrulation. On a methodological level, we provide a statistical tool that infers TE-dependent cis-regulation from RNA-seq data alone, thus facilitating the study of TEs in the next-generation sequencing era. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-03085-7. BioMed Central 2023-11-10 /pmc/articles/PMC10637000/ /pubmed/37950299 http://dx.doi.org/10.1186/s13059-023-03085-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Pulver, Cyril
Grun, Delphine
Duc, Julien
Sheppard, Shaoline
Planet, Evarist
Coudray, Alexandre
de Fondeville, Raphaël
Pontis, Julien
Trono, Didier
Statistical learning quantifies transposable element-mediated cis-regulation
title Statistical learning quantifies transposable element-mediated cis-regulation
title_full Statistical learning quantifies transposable element-mediated cis-regulation
title_fullStr Statistical learning quantifies transposable element-mediated cis-regulation
title_full_unstemmed Statistical learning quantifies transposable element-mediated cis-regulation
title_short Statistical learning quantifies transposable element-mediated cis-regulation
title_sort statistical learning quantifies transposable element-mediated cis-regulation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637000/
https://www.ncbi.nlm.nih.gov/pubmed/37950299
http://dx.doi.org/10.1186/s13059-023-03085-7
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