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Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors

Jönsson, Marie E. LU ; Ludvik Brattås, Per LU ; Gustafsson, Charlotte; Petri, Rebecca LU ; Yudovich, David LU ; Pircs, Karolina LU ; Verschuere, Shana LU ; Madsen, Sofia LU ; Hansson, Jenny LU and Larsson, Jonas LU , et al. (2019) In Nature Communications 10(1).
Abstract

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... (More)

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.

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@article{cc4c8e8b-a96d-4008-9b4f-0eaa4ab2af3c,
  abstract     = {<p>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.</p>},
  articleno    = {3182},
  author       = {Jönsson, Marie E. and Ludvik Brattås, Per and Gustafsson, Charlotte and Petri, Rebecca and Yudovich, David and Pircs, Karolina and Verschuere, Shana and Madsen, Sofia and Hansson, Jenny and Larsson, Jonas and Månsson, Robert and Meissner, Alexander and Jakobsson, Johan},
  issn         = {2041-1723},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors},
  url          = {http://dx.doi.org/10.1038/s41467-019-11150-8},
  volume       = {10},
  year         = {2019},
}