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

• Published in: Nature communications Vol. 10; no. 1; pp. 3182 - 11
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-07-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/100; 13/106; 13/31; 13/44; 13/51; 14/63; 38/23; 38/91; 45/15; 45/77; 631/378/2583; 631/378/2584; 82/58; 82/80; Basic Medicine; Brain; Brain - embryology; Cell and Molecular Biology; Cell- och molekylärbiologi; Cells (biology); Chromatin Assembly and Disassembly - genetics; Chromatin remodeling; CpG islands; CpG Islands - genetics; CRISPR; CRISPR-Cas Systems - genetics; Deactivation; Demethylation; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA Demethylation; DNA methylation; DNA Methylation - genetics; DNA methyltransferase; DNMT1 protein; Gene Silencing - physiology; Genes; Humanities and Social Sciences; Humans; Inactivation; Long interspersed nucleotide elements; Long Interspersed Nucleotide Elements - genetics; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; multidisciplinary; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Progenitor cells; Proteins; Science; Science (multidisciplinary); Somatic cells; Transcription activation; Transcriptional Activation - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11150-8

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.
DNA methylation plays an important role in silencing transposable elements. Here the authors find that loss of DNMT1 and DNA methylation leads to transcriptional activation and chromatin remodelling of evolutionarily young—hominoid-specific —LINE-1 elements which then act as alternative promoters for neuronal genes.