PhD Studentship: Functional genomic approaches to convergent mechanisms in chromatinopathies

Background

Chromatinopathies is a group of more than 180 rare genetic disorders caused by variants in genes encoding chromatin remodelling factors . Collectively, these disorders are amongst the most prevalent genetic conditions and are often characterised by neurodevelopmental features including developmental delay, intellectual disability and autism. Currently, no treatments exist for most chromatinopathies. Developing a personalised, targeted treatment for each of chromatinopathy represents a major, if not an impossible task. We hypothesised that the mechanisms of some chromatinopathies converge on overlapping pathways raising the possibility that the same drugs could potentially treat several chromatinopathies. Indeed, our initial studies have shown that the same class of drugs can rescue neurodevelopmental phenotypes in relevant mouse models. This opens an exciting opportunity to use functional genomics to investigate the fundamental biology of this important group of disorders and fulfil a major unmet medical need by discovering new treatments.

Key question and objectives

We have prioritised three related chromatinopathies to study in this project. The key question of this project is “What are the transcriptomic and epigenomic changes in the brain that characterise these chromatinopathies and how do they respond to treatment?”

Specific objectives are:

1. To identify the cell types, genes and chromatin changes that characterise each of these chromatinopathies and identify convergent pathways in relevant mouse models.
2. To test how treatment modifies the transcriptomic and epigenomic landscape in the brains of these mouse models.
3. To test is the treatment can rescue behavioural phenotypes in the mouse models.

Methodology

The student will work closely with an expert post-doctoral scientist in the lab and will use a range of next generation sequencing based approaches to investigate the effects of these treatments on the epigenome and transcriptome and mouse behavioural assessments. The sequencing data for some of these experiments have already been collected and can be analysed straight away.

Parse snRNAseq will be used to compare gene expression differences in cell types of the mouse frontal cortex in mice, bulk RNA-seq to detect global transcriptional changes and CUT&Tag-seq to compare effects on the hypothesised convergent chromatin alterations.

Mouse behavioural tests will be employed to determine if key neurodevelopmental phenotypes in defined mouse models can be rescued by drug treatment. Tests for anxiety, activity, repetitive behaviours, social behaviours, motor function and learning and cognitive tests to assess learning and memory will be used.

Equivalent samples from mouse frontal cortex treated with drug will be analysed in parallel to identify the convergent molecular targets of drug treatment. Data from human neurons, from patient-derived and control induced pluripotent stem cells (hiPSCs) treated with the same drug is also available and can be compared directly with the data from the mouse models.

Expected outcomes

We expect to show that a single drug can rescue behavioural phenotypes in mouse models of several chromatinopathies and identify convergent epigenetic mechanisms that respond to the same drug to normalise aberrant gene expression in the frontal cortex.

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