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

Heterochromatin is characterised by an inaccessibility to the transcriptional machinery and associated with the histone mark H3K9me3. Heterochromatin erosion is a hallmark of human ageing and H3K9me3 is lost globally in aged mammalian cells. However, the functional consequences of the loss of heterochromatin maintenance have been challenging to model. In this study, we used CRISPRi-mediated deletion of the H3K9me3 methyltransferase SETDB1 in human neural progenitor cells to model disruption of heterochromatin maintenance. Deletion of SETDB1 had a limited effect on cell viability, despite a global loss of H3K9me3 peaks resulting in genome-wide reorganization of heterochromatin domains, cells remained proliferative and expressed appropriate marker genes. We found that a key event following the loss of H3K9me3 maintenance was the expression of evolutionarily young L1 retrotransposons. Derepression 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. In conclusion, these results demonstrate that loss of H3K9me3 in human neural somatic cells transcriptionally activates evolutionary young L1 retrotransposons, further implicating these elements in human ageing processes.