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Loss of H3K9me3 maintenance leads in human neural progenitor cells leads to transcriptional activation of L1 retrotransposons [Bulk RNA-seq]

ABSTRACT: We used CRISPRi-mediated deletion of the H3K9me3 methyltransferase SETDB1 in a human neural epithelial-like stem cell line with the characteristics of human neural progenitor cells (hNPCs) to model disruption of heterochromatin maintenance. We found that a key event following the loss of H3K9me3 maintenance was the expression of evolutionary young full-length L1 elements. Transcriptional activation of L1s was associated with a loss of CpG DNA methylation at their promoters, suggesting that deposition of H3K9me3 at the L1 promoter is required to maintain DNA methylation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292899 | GEO | 2026/02/11

REPOSITORIES: GEO

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

Project description:DNA methylation is an important epigenetic modification that is thought to contribute to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements (TEs). In this study we used CRISPR/Cas9 mediated gene editing to disrupt DNMT1, the key maintenance methyltransferase in somatic human cells. Surprisingly, and in contrast to findings in mouse, inactivation of DNMT1 in human neural progenitor cells (hNPCs) resulted in viable proliferating cells that maintained the expression of appropriate marker genes. Removal of DNA methylation in hNPCs resulted in a specific activation of hominid-specific LINE-1 elements (L1s), while other classes of TEs remained silent. We also found that the transcriptionally activated L1s acted as alternative promoters for many protein-coding genes involved in neuronal functions, uncovering an L1-based transcriptional network influencing neuronal protein-coding genes. Our results prove novel mechanistic insight into the role of DNA methylation in somatic human cells.

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

Project description:DNA methylation is thought to contribute to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements (TEs). In this study, we used CRISPR/Cas9 technology to delete DNMT1, the key maintenance DNA methyltransferase in human neural progenitor cells (hNPCs). Surprisingly, and in contrast to previous findings in mouse somatic cells, inactivation of DNMT1 in hNPCs resulted in viable proliferating cells despite the global loss of DNA CpG-methylation. DNA demethylation led to specific transcriptional activation and chromatin remodeling of evolutionarily young, hominoid-specific LINE-1 elements (L1s), while older L1s and other classes of TEs remained silent. The activated L1s acted as alternative promoters for many protein-coding genes involved in neuronal functions, revealing a hominoidspecific L1-based transcriptional network controlled by DNA methylation that influences neuronal protein-coding genes. Our results give a novel mechanistic insight into the role of DNA methylation in silencing TEs in somatic human cells, as well as further implicating L1s in human brain development and disease.

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