Epigenetics and neurodevelopmental disorder: molecular and behavioural characterisation of an Ehmt1/Glp knockout mouse model

EHMT1 encodes the histone methyltransferase GLP (G9a-like protein) and has been implicated in the aetiology of a number of neurodevelopmental disorders including Kleefstra syndrome, autism and schizophrenia (Talkowski et al., 2012). Histone methyltransferase is a crucial epigenetic process for transcriptional silencing and via its methyltransferase activity GLP targets Histone H3 Lys 9 (H3-K9) both independently and as a heteromeric complex with G9a (Tachibana et al., 2005). Recent in vitro work by a PhD student in our lab has shown that haploinsufficiency of Ehmt1/Glp in ES cells retards their progression to neural precursors and, ultimately, neurons. Moreover, expression of this protein peaks at critical time-points in brain development and is restricted to areas of neurogenesis in the adult brain. Taken together, these data suggest that Glp is a key factor regulating neural development.

This PhD project is focused on examining the functional consequences of Ehmt1/Glp haploinsufficiency. Using a conditional knockout model, the Ehmt1D6cre/+ mouse, we have shown that restricting deletion to the forebrain results in changes in activity levels, anxiety, startle response and prepulse inhibition of startle. We now want to examine aspects of cognition in these mice, including executive function (reversal learning). In addition, this project will also examine the molecular changes in the adult brain that may underpin these behavioural differences, looking at changes in gene expression and chromatin architecture (e.g. RNA-seq and FAIRE-seq). Finally, the student will also examine the effect of Ehmt1/Glp haploinsufficiency on adult neurogenesis, in response to pharmacological and environmental stimulation. Neurogenesis may also be examined at the behavioural level by examining pattern-separation behaviour in the Ehmt1D6cre/+ mouse.

Please send a CV and a covering letter to [Email Address Removed]