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.
Highlights
DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements
We transduced the fetal-derived human neural progenitor cells (hNPCs) line Sai[2], which has the characteristics of neuroepithelial-like stem cells[23], with LV.CRISPR-DNA methyltransferase 1 (DNMT1) followed by FACS-GFP isolation 10 days later (Fig. 1a)
We found that protein-coding genes located within 50 kb of activated L1HS, L1PA2, or L1PA3 were significantly upregulated in DNMT1-KO hNPCs, while genes located close to human endogenous retrovirus (HERV) and SVAs were not (Fig. 3a, b)
Summary
DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements. 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. Despite a global loss of CpG-methylation, hNPCs lacking DNMT1 activity survive and remain proliferative, thereby providing an excellent model system for investigating the role of DNA methylation in the control of TEs in somatic cells. The activated L1s serve as alternative promoters for many nearby protein-coding genes previously identified as being involved in neuronal functions and psychiatric disorders These results provide a fundamental mechanistic insight into the role of DNA methylation in transcriptional control of TEs in human somatic cells and describe a mechanism for how L1 activation influences human brain development and related disorders through its impact on gene regulatory networks
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