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My research in a nutshell

How multicellular organisms, with their elaborate pattern and diverse array of cell-types, arise during development from a single cell is a fascinating and complex process. Given that all cells in a developing human embryo share the same genome, differential utilisation of a limited set of genes is key for driving the observed cellular diversity. To orchestrate cell-type specific patterns of gene expression, non-coding regulatory elements called enhancers act as regulatory switches, turning genes on and off in time and space during development. Our lab investigates mechanisms of gene regulation in the context of craniofacial development, and how enhancer perturbation can lead to human congenital craniofacial disorders.

 

The vertebrate face largely develops from a transient embryonic cell-type called the cranial neural crest. To study human facial development we utilise both in vitro differentiation of human embryonic stem cells to cranial neural crest cells (CNCCs) and animal models coupled to genome-editing, epigenomic analysis and imaging based approaches. In recent work, we focused on understanding the regulatory mechanisms driving expression of an important developmental transcription factor called SOX9 whose perturbation causes craniofacial dysmorphology. We identified clusters of extreme long-range enhancers over a million base pairs upstream of the SOX9 gene that are active in CNCCs, exhibit features of synergistic gene regulation and whose ablation recapitulates aspects of a human craniofacial disorder.

 

Leveraging this interesting regulatory domain, we are now investigating how chromosomal structure relates to gene activity using genetic engineering and imaging approaches. We are also investigating how multiple enhancers act in combination both within clusters of enhancers and across a regulatory locus, and are seeking to identify sequence features and position effects that influence enhancer combinatorial behaviour. Ultimately our work will further our understanding of enhancer function during normal development, and help us to predict how non-coding genetic mutations may impact developmental gene expression and drive disease phenotypes.

Biography

Starting in school I took an active interest in research, and spent a memorable summer supported by a Nuffield Science Bursary to investigate the impact of invasive crayfish species on native populations. I undertook my undergraduate studies at the University of Cambridge in the Natural Sciences, taking further opportunities to conduct research with Professor Leonard Zon at Harvard Stem Cell Institute and Professor Akira Nakamura at the RIKEN Institute in Japan. Based on my interests in development and nuclear processes, I embarked upon my doctoral work at the University of Oxford, Department of Biochemistry as a student in the Wellcome Trust Graduate Programme in Chromosome and Developmental Biology. During my DPhil, I worked with Professors Rob Klose and Roger Patient to uncover conservation of non-methylated islands across vertebrate species and interrogated DNA sequence features that contribute to DNA methylation status.

 

For my postdoc, I was awarded a Sir Henry Wellcome post-doctoral research fellowship and worked with Professor Joanna Wysocka at Stanford University in collaboration with Professors Doug Higgs and Jim Hughes at the University of Oxford. In my post-doctoral work, I utilised human embryonic stem cell and murine models to functionally characterise gene regulatory regions, called enhancers, that are perturbed in patients with an isolated craniofacial disorder called Pierre Robin sequence (PRS). In this work we provided molecular insights into disease mechanisms, characterised extreme long-range disease-associated enhancers for the SOX9 gene and highlighted how subtle alteration of gene expression can drive morphological change.

 

As a Programme Leader Track (PLT) Group Leader at the MRC Human Genetics Unit, my group will now leverage our depth of knowledge at the SOX9 regulatory locus, and developed model systems, to investigate how combinatorial enhancer function and 3D genome architecture contribute to gene regulation. Our work will have important implications for understanding how genetic alterations impact normal-range human facial development and can contribute to disease.

Websites

Education/Academic qualification

Wellcome Trust Graduate Programme in Chromosome and Developmental Biology, Doctor of Philosophy (PhD), University of Oxford

Award Date: 1 Jul 2014

Natural Sciences, Bachelor of Arts, University of Cambridge

Award Date: 1 Jul 2009

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