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

Marie E Jönsson, Per Ludvik Brattås, Charlotte Gustafsson, Rebecca Petri, David Yudovich, Karolina Pircs, Shana Verschuere, Sofia Madsen, Jenny Hansson, Jonas Larsson, Robert Månsson, Alexander Meissner and Johan Jakobsson ()
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Marie E Jönsson: Lund University
Per Ludvik Brattås: Lund University
Charlotte Gustafsson: Karolinska Institute
Rebecca Petri: Lund University
David Yudovich: Lund University
Karolina Pircs: Lund University
Shana Verschuere: Lund University
Sofia Madsen: Lund University
Jenny Hansson: Lund University
Jonas Larsson: Lund University
Robert Månsson: Karolinska Institute
Alexander Meissner: Max Planck Institute for Molecular Genetics
Johan Jakobsson: Lund University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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 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.

Date: 2019
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DOI: 10.1038/s41467-019-11150-8

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