SIDB project - Epigenetic balance in the developing brain – Understanding how the loss of opposing chromatin modifiers leads to convergent pathophysiology

SIDB project - Epigenetic balance in the developing brain – Understanding how the loss of opposing chromatin modifiers leads to convergent pathophysiology

Project Code: 

During embryonic development the formation of the human brain requires a balance between the expansion and differentiation of neural stem cells. This is coordinated by key transcription factors which operate in concert with the epigenome to drive appropriate gene expression programmes. Consequently, loss of function mutations in chromatin modifier proteins are a prominent cause of neurodevelopmental disorders (NDDs) such as ASD. Disruption of enzymes involved in both the deposition and erasure of chromatin modifications suggests that NDDs may arise from a general loss of epigenetic fidelity and consequently in an inability to respond proportionately to signalling cues which drive neurodevelopment1. This can be viewed as the ‘Goldilocks principle’ where too much or too little is equally bad for the developing brain. 

How then, do opposing molecular activities lead to a common pathophysiology? To address this question, the student will employ a synthetic degron tagging strategy in human induced pluripotent stem cells (iPSCs) to allow acute and reversible protein depletion. Targeting will be performed on pairs of genes which are mutated in NDDs and which encode proteins that deposit and erase the same histone modification. The impact of perturbing these reciprocal activities will then be modelled in cerebral organoids differentiated from iPSCs2. Immuno-imaging and genomics approaches will be used to determine how loss of these modifiers impacts on cortical development; both in terms of cellular proliferation vs. differentiation and the regulation of transcription. This approach also allows for the controllable restoration of de-stabilised proteins and thus provides the means to determine if normal development can be recovered following loss of function; an important factor when considering therapeutic interventions in the future. Using complementary approaches in chromatin3and neurodevelopmental biology, the student will be well positioned to address fundamental questions regarding the molecular aetiology of NDDs which arise from perturbed epigenetic regulation.

Relevant references:

Garay, P.M., Wallner, M.A. and Iwase, S. (2016) Yin-yang actions of histone methylation regulatory complexes in the brain. Epigenomics 8(12): 1689–1708.

Mason, J.O. and Price, D.J. (2016) Building brains in a dish; prospects for growing cerebral organoids from stem cells Neuroscience 334: 105-118

Illingworth, R.S., Hölzenspies, J.J., Roske, F.V., Bickmore, W.A. and Brickman J.M. (2016) Polycomb enables primitive endoderm lineage priming in embryonic stem cells. ELife 5: e14926.

Additional Project Info 
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Primary Host Research Centre 
Funding Status of this Project 
This project will accept a self-funded student
Deadline for Application 
Monday, 14 January, 2019
Research Area(s) 
Intellectual disability