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Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors
DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements. In this study, we use CRISPR-Cas9 technology to delete DNMT1, the DNA methyltransferase key for DNA methylation maintenance, in human neural progenitor cells...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639357/ https://www.ncbi.nlm.nih.gov/pubmed/31320637 http://dx.doi.org/10.1038/s41467-019-11150-8 |
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author | Jönsson, Marie E Ludvik Brattås, Per Gustafsson, Charlotte Petri, Rebecca Yudovich, David Pircs, Karolina Verschuere, Shana Madsen, Sofia Hansson, Jenny Larsson, Jonas Månsson, Robert Meissner, Alexander Jakobsson, Johan |
author_facet | Jönsson, Marie E Ludvik Brattås, Per Gustafsson, Charlotte Petri, Rebecca Yudovich, David Pircs, Karolina Verschuere, Shana Madsen, Sofia Hansson, Jenny Larsson, Jonas Månsson, Robert Meissner, Alexander Jakobsson, Johan |
author_sort | Jönsson, Marie E |
collection | PubMed |
description | DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements. In this study, we use CRISPR-Cas9 technology to delete DNMT1, the DNA methyltransferase key for DNA methylation maintenance, in human neural progenitor cells (hNPCs). We observe that inactivation of DNMT1 in hNPCs results in viable, proliferating cells despite a global loss of DNA CpG-methylation. DNA demethylation leads to specific transcriptional activation and chromatin remodeling of evolutionarily young, hominoid-specific LINE-1 elements (L1s), while older L1s and other classes of transposable elements remain silent. The activated L1s act as alternative promoters for many protein-coding genes involved in neuronal functions, revealing a hominoid-specific L1-based transcriptional network controlled by DNA methylation that influences neuronal protein-coding genes. Our results provide mechanistic insight into the role of DNA methylation in silencing transposable elements in somatic human cells, as well as further implicating L1s in human brain development and disease. |
format | Online Article Text |
id | pubmed-6639357 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66393572019-07-22 Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors Jönsson, Marie E Ludvik Brattås, Per Gustafsson, Charlotte Petri, Rebecca Yudovich, David Pircs, Karolina Verschuere, Shana Madsen, Sofia Hansson, Jenny Larsson, Jonas Månsson, Robert Meissner, Alexander Jakobsson, Johan Nat Commun Article DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements. In this study, we use CRISPR-Cas9 technology to delete DNMT1, the DNA methyltransferase key for DNA methylation maintenance, in human neural progenitor cells (hNPCs). We observe that inactivation of DNMT1 in hNPCs results in viable, proliferating cells despite a global loss of DNA CpG-methylation. DNA demethylation leads to specific transcriptional activation and chromatin remodeling of evolutionarily young, hominoid-specific LINE-1 elements (L1s), while older L1s and other classes of transposable elements remain silent. The activated L1s act as alternative promoters for many protein-coding genes involved in neuronal functions, revealing a hominoid-specific L1-based transcriptional network controlled by DNA methylation that influences neuronal protein-coding genes. Our results provide mechanistic insight into the role of DNA methylation in silencing transposable elements in somatic human cells, as well as further implicating L1s in human brain development and disease. Nature Publishing Group UK 2019-07-18 /pmc/articles/PMC6639357/ /pubmed/31320637 http://dx.doi.org/10.1038/s41467-019-11150-8 Text en © The Author(s) 2019 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Jönsson, Marie E Ludvik Brattås, Per Gustafsson, Charlotte Petri, Rebecca Yudovich, David Pircs, Karolina Verschuere, Shana Madsen, Sofia Hansson, Jenny Larsson, Jonas Månsson, Robert Meissner, Alexander Jakobsson, Johan Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors |
title | Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors |
title_full | Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors |
title_fullStr | Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors |
title_full_unstemmed | Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors |
title_short | Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors |
title_sort | activation of neuronal genes via line-1 elements upon global dna demethylation in human neural progenitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639357/ https://www.ncbi.nlm.nih.gov/pubmed/31320637 http://dx.doi.org/10.1038/s41467-019-11150-8 |
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