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Smchd1 is an epigenetic repressor, targetable by small molecules and known to play a role in silencing PWS cluster genes on the maternal allele in mice. We are working on proof-of-concept data for gene reactivation using SMCHD1 as a target for potential therapy. Removal of Smchd1in vitro has been shown to result in activation of the silent maternally inherited copy of PWS genes at the proximal end of the cluster. Using a reporter mouse model for Magel2 expression we have shown that in line with previous data deletion of Smchd1 can result in reactivation of maternally inherited PWS genes in vivo in the brain, specifically in the hypothalamus. Furthermore, in hypothalamic tissue we see reactivation of PWS genes not only from the proximal end of the cluster but from the distal end as well, with seemingly no effect on Ube3a expression. To determine whether the level of reactivation we observe is sufficient to rescue disease phenotypes in the Magel2 paternal-null model we have begun behavioural and motor testing using mice that have had Smchd1 deleted in the brain, looking at features of PWS within the cohort. From this we aim to increase understanding of the molecular mechanisms at work within the PWS cluster and to confirm viability of SMCHD1 as a target for epigenetic therapy of PWS.
Megan completed a Masters of Science at the University of Auckland in 2017. She is currently in her 3rd year of PhD in the Blewitt lab at WEHI. Her PhD research is focussed on the epigenetic regulator SMCHD1 as a potential target for therapy of the neurodevelopmental imprinting disorders Prader-Willi Syndrome and Schaaf-Yang Syndrome.