We have successfully completed our research goals across all three aims:
For Aim 1, which investigates whether MYT1L depletion leads to loss of neuronal identity and mental disorders, we have generated and studied new Myt1l knockout mouse models and CRISPR-engineered human induced neurons. MYT1L-deficient mice displayed striking neurological and behavioural phenotypes resembling MYT1L syndrome in patients, including impaired social behaviour and altered neuronal gene expression. Importantly, we showed that MYT1L-deficient human neurons exhibit similar molecular and electrophysiological defects. An unexpected key finding was that these neuronal dysfunctions can be reversed by acutely applying an FDA-approved anti-epileptic drug (Weigel et al., Molecular Psychiatry 2023). Our data now demonstrate for the first time that MYT1L haploinsufficiency can cause neurodevelopmental disorders, but also reveal that treatment options for these conditions exist.
For Aim 2, which focuses on the mechanistic link between safeguard repressors and the epigenetic machinery, we identified interaction partners of MYT1L directly in human neurons (Weigel et al., Molecular Psychiatry 2023). We found that MYT1L associates with chromatin regulators implicated in autism spectrum disorders, suggesting that they function together to maintain proper neuronal development. Using genetic rescue experiments, we further demonstrated that overexpression of MYT1L in mature neurons can restore neuronal function, suggesting its lifelong role in safeguarding neuronal identity.
For Aim 3, which seeks to identify safeguard repressors in non-neuronal cell types, we predicted safeguard repressors across 18 cell types. Our experimental validation identified PROX1 as a liver-specific safeguard repressor that stabilizes hepatocyte identity by directly suppressing alternative gene programs. We showed that PROX1 is required for liver regeneration and prevents tumour formation in vivo. Conversely, Prox1 loss destabilizes liver identity and promotes tumour progression, consistent with clinical observations (Lim et al., Nature Genetics 2025). These results were published and resulted in a priority patent filing for potential liver cancer therapies. Moreover, this work initiated new research directions exploring the role of safeguard repressors in brain cancer, specifically glioblastoma.
