Our work centres on two questions:
How does regulatory DNA control gene expression in the human brain?
and
What happens when it goes wrong?
We approach this using human iPSC-derived brain cells, which let us study regulatory mechanisms in the relevant human cell types and edit the genome to test cause and effect directly.
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Mapping the regulatory genome of the human brain
Mapping the regulatory genome of the human brain
Enhancers rarely sit next to the genes they control. They can act across hundreds of kilobases and skip over intervening genes entirely, so knowing where an enhancer isdoesn't tell you what it does. Therefore as well as annotating candidate regulatory elements in the human brain, we aim to connect them to their targets.
We develop and apply methods, including ViCAR, that capture the physical contacts between regulatory elements and gene promoters, and we generate these maps across the neural cell types in which disease genes are active. The aim is a cell-type-resolved picture of which element controls which gene, and how that wiring differs between a neuron, an astrocyte and a microglial cell.
Questions we're asking
Which enhancers contact which genes, and in which cell types?
How does regulatory wiring change as neural cells differentiate?
How enhancers work
How enhancers work
The best way to know what a regulatory element does is to remove it and see what happens.
We use CRISPR-based perturbation to test regulatory DNA directly. Beyond testing function, we want to know why: what makes it active in one cell type and not another, how it communicates with a distant promoter, and which proteins and chromatin features that communication actually requires.
Questions we're asking
What makes an enhancer active in one cell type and silent in another?
Are we missing functional regulatory elements because they lack the marks we look for?
Which chromatin features and proteins are actually required, rather than merely present?
3D architecture and the machinery that builds it
3D architecture and the machinery that builds it
Enhancer–promoter communication depends on how the genome is folded. Chromatin loops and topologically associating domains bring distant elements together and keep others apart, and this architecture is remodelled as neural cells develop. We study the proteins and DNA features that create this organisation.
Questions we're asking
How does genome folding create cell-type-specific gene expression?
How does genetic variation in the machinery that organises genome folding lead to brain disorders?
Can the molecular consequences of disrupted architecture be reversed?
Our funders
Our funders
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