The brain is the most complex organ in the human body where billions of interconnected neurons provide the framework for us to interpret our environment, instruct other organs, and enable intellectual thought which uniquely defines our human qualities. Development of the brain, termed ‘neurodevelopment,’ is a highly organised process governed at the molecular level by epigenetics - a cellular process regulating which genes to silence and activate. Epigenetic regulatory proteins are responsible for silencing non-neural genes and activating transcriptional programmes driving neurodevelopment in a temporal and spatial manner to ensure the brain develops and matures correctly.

What happens when epigenetics goes wrong? The brain is highly susceptible to loss-of-function in epigenetic genes, even when a single allele is not functional. A growing body of evidence has linked errors in over 70 epigenetic regulator genes to neurodevelopmental disorders resulting in intellectual disability. Beyond clinical and behavioural assessment, little is known about how these genetic errors affect neurodevelopment and neurobiology in these individuals.

This PhD project is focused on a class of epigenetic neurodevelopmental disorders affecting the KMT2 family of histone methyltransferase genes - an epigenetic process which adds methyl groups to histone tails. 6/7 members of this family are associated with a neurodevelopmental disorder resulting in lifelong intellectual disability. This project will involve using CRISPR/Cas9-mediated gene editing in human pluripotent stem cells to generate genetic models of the KMT2 neurodevelopmental disorders, differentiating these models into neurons, assess neurobiological phenotypes including neuronal activity, synaptogenesis, and neurite morphology and multi-omic analysis including RNAseq, CUT&Tag and ATACseq. This program of work will determine how molecular pathology of these disorders culminate into cellular pathology and to what degree these disorders overlap in molecular and cellular phenotypes. This PhD project will provide vital information into these neurodevelopmental disorders and the role histone methylation plays in neurodevelopment.

If you are interested in this PhD project, send an email to Prof Paul Lockhart (primary supervisor, paul.lockhart@mcri.edu.au) explaining why you would like to be considered for this opportunity and how the project fits with your experience and interests. Make sure to attach your CV and transcripts to the email. Only enquiries sent via email will be considered.

Mr

Jordan Wright

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Department of Paediatrics

Mr

Jordan Wright

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