Epigenetic silencing is a fundamental process critical for normal development that has been the focus on my group’s research. In this talk I’d like to focus on how we can use this knowledge to identify and test new ideas for how to treat incurable diseases. In this case,I will focus on the neurodevelopmental disorder Prader Willi syndrome (PWS) that currently has no effective treatment. PWS is caused by lack of expression of a suite of genes on chromosome 15, whose expression is exclusively derived from the paternal allele due to genomic imprinting. Since all patients harbour the maternal epigenetically silenced allele, a potential therapeutic approach that targets the underlying cause of disease is to activate expression from the maternal allele by inhibiting its epigenetic silencing. Evidence from other neurodevelopmental syndrome suggests intervention in the neonatal period could have beneficial effects, likely because brain development is still ongoing.

We are working on SMCHD1, which we have previously shown silences the PWS cluster in mice, as well as the Hox genes and several other autosomal clustered gene families, alongside the inactive X chromosome in females. In this talk I will present our current evidence from mouse and human studies relating to SMCHD1 as a drug target for Prader Willi syndrome. While SMCHD1 is essential for gene silencing at all its targets during early embryonic development, we have found that removing SMCHD1 after this stage, at a time and in a tissue relevant to disease treatment, has very limited effects on gene expression. This reveals interesting aspects of the different stages of epigenetic control, pertinent to disease treatment more broadly. Importantly for us, the PWS cluster of genes remains sensitive to removal of SMCHD1 in the neural system both in vivo in mice and in Prader-Willi patient iPS cell-derived neural progenitors. These data suggest that SMCHD1 may indeed be a relevant drug target for Prader Willi syndrome.