Loss of H3K9me3 maintenance leads in human neural progenitor cells leads to transcriptional activation of L1 retrotransposons

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.