Epigenetic regulation of transposable elements in human brain development and disease

Transposable elements (TEs) are mobile genetic sequences comprising around 50% of human DNA. TEs shape gene regulatory networks in development, pluripotency and inflammation, and are implicated in a number of neurological disorders. Therefore, TEs are tightly controlled by epigenetic regulators which form a complex repressive network throughout different stages of development. However, while the repressive mechanisms controlling TEs have been extensively studied, the interplay between these mechanisms and their relevance to human disease remain largely unknown. In this thesis we systematically investigate the effects of depletions and patient mutations in epigenetic regulators of TEs in early human brain development, with a particular focus on heterochromatin. We found that maintaining TE silencing depends on an intricate interaction between HUSH-MORC2 corepressor, DNA methylation and H3K9me3 in human pluripotent stem cells and neural progenitor cells. We identified a mechanistic hierarchy in epigenetic TE regulation by these pathways during early human neurodevelopment (paper I, II, and III). We modelled mutations in key TE regulators found in patients with neurodevelopmental disorders and measured the consequences for TE activity and downstream changes in gene expression programs specific for neural lineages and genomic integrity (paper II, and IV). Together, our findings reveal the interplay of epigenetic TE repressors and the consequences of their malfunction during early human brain development and suggest that TE activity could play a significant role in human neurodevelopmental disorders.