Epigenetics and neurodevelopmental disorders: Molecular and behavioural characterisation of an Ehmt1/Glp knockout mouse model

Post-translational histone modifications lead to large coordinated and dynamic changes to the chromatin in a spatial and temporally specific manner. These highly synchronised epigenetic changes control gene transcription and are critical for various cellular functions including cell cycle progression, DNA repair, and telomere maintenance. The role of epigenetics in neurodevelopment is wide-ranging therefore it is highly unsurprising that epigenetic modifiers have been implicated in neurodevelopmental disorders (NDDs). I used an in vivo and in vitro approach to understand the role of histone modifier Ehmt1 in development and disorder. In this thesis I describe a distinct behavioural phenotype in a forebrain specific Ehmt1 haploinsufficient mouse model, Ehmt1D6cre/+ (Chapters 2 & 3). These behavioural findings were then related to the role of Ehmt1 in adult hippocampal neurogenesis, in vivo (Chapter 4) and in vitro (Chapter 5). Finally using publically available RNA-seq data, enrichment analyses were used to determine the effect of Ehmt1 reduction on key phenotypes associated with memory and learning, as well as identifying genes associated with neurodevelopmental disorders (Chapter 6). In summary, this thesis aims to draw connections between Ehmt1’s function in the forebrain, particularly the hippocampus, and the deficits seen in cognition and executive functioning in a number of associated neurodevelopmental disorders. Using interesting results from data mining, along with findings from behavioural and cellular analyses; identification of potential downstream targets for further research of disease pathogenesis could be possible