- Sir Henry Wellcome Postdoctoral Fellow at the MRC Weatherall Institute
- Fulford Junior Research Fellow at Somerville College
Advanced Python for Bioinformatics
Due to the shutdown of the WIMM by COVID-19, I will be running the "Advanced Python for Bioinformatics" course online using datacamp (https://www.datacamp.com/). The course is open to all DPhil students at the WIMM and will begin on Monday April 6th. Further details will be circulated via email.
I am a Sir Henry Wellcome Postdoctoral Fellow working with Prof. Doug Higgs in the MRC Haematology Unit on regulatory regions of DNA called enhancers and how they function to regulate gene expression.
I studied Biochemistry as an undergraduate at Cambridge University and completed my PhD at Imperial college supervised by Prof. Ana Pombo, who subsequently moved to the Max Delbruck Centre in Berlin.
Genome Architecture Mapping (GAM)
For my Doctoral project, I developed Genome Architecture Mapping (GAM), a new technology for measuring the complex folding of DNA in the 3D space of the nucleus. GAM works by isolating hundreds of thin slices from individual nuclei and sequencing their DNA content. Genomic regions which are close in the nucleus will be found together in the same thin nuclear slice more often than regions which are distant. Importantly, this approach is readily applicable to fixed tissue, and could therefore be an important tool for identifying the targets of sequence variants implicated in human disease.
To test this new method, I applied GAM to mouse embryonic stem (mES) cells by sequencing DNA from around 500 mES nuclear slices and generating a map of DNA folding. In collaboration with Dr. Antonio Scialdone and Prof. Mario Nicodemi (University of Naples) we developed a statistical model to identify DNA regions that interacted in threes, rather than in pairs. Remarkably, we found thousands of triplets throughout the mES cell genome, suggesting that multi-way contacts are a prevalent and potentially important feature of chromatin folding. By searching for common features, we found that triplets are especially likely to form between the strongest enhancers, so-called super-enhancers1.
GAM holds the potential to detect enhancer-gene interactions in rare cell types that are currently difficult to study using alternative approaches. Many of these rare cells are affected in genetic disease, and the ability to connect sequence variants to the genes whose expression they affect will provide new insights crucial for developing diagnostic and therapeutic interventions.
Enhancer function in erythropoiesis
Whilst working on GAM I developed a passion for enhancer biology and a keen interest in the mechanism by which enhancers activate expression of their target genes. My Sir Henry Wellcome Postdoctoral Fellowship project aims to dissect the mechanisms driving gene activation by enhancers during red blood cell differentiation. The project began in April 2018 and will be carried out in collaboration with Assoc. Prof. Merav Socolovsky (UMass Medical School).
The Socolovsky Lab has identified an intriguing transition point during mouse red blood cell differentiation in which early red blood cell progenitors begin replicating their DNA at precisely the same moment that they activate many genes required for their terminal differentiation2. Cells also replicate DNA faster during this specific cell cycle than the cycles that precede or follow it3.
My project will identify the genes activated during this transition and the enhancers that regulate them by using global approaches to measure changes in DNA folding, binding of regulatory proteins to enhancers and gene activity. Applying these approaches to a gene activation event that occurs during a single cell cycle will give me unique temporal precision.
1. R. A. Beagrie et al., Complex multi-enhancer contacts captured by genome architecture mapping. Nature. 543, 519–524 (2017).
2. R. Pop et al., A Key Commitment Step in Erythropoiesis Is Synchronized with the Cell Cycle Clock through Mutual Inhibition between PU.1 and S-Phase Progression. PLoS Biol. 8, e1000484 (2010).
3. Y. Hwang et al., Global increase in replication fork speed during a p57 KIP2 -regulated erythroid cell fate switch. Sci. Adv. 3, e1700298 (2017).
Reactivation of a developmentally silenced embryonic globin gene.
King AJ. et al, (2021), Nat Commun, 12
Enhancers predominantly regulate gene expression during differentiation via transcription initiation.
Larke MSC. et al, (2021), Mol Cell, 81, 983 - 997.e7
High-resolution targeted 3C interrogation of cis-regulatory element organization at genome-wide scale.
Downes DJ. et al, (2021), Nat Commun, 12
The mouse alpha-globin cluster: a paradigm for studying genome regulation and organization.
Oudelaar AM. et al, (2020), Curr Opin Genet Dev, 67, 18 - 24
Recapitulation of erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I) identifies defects in differentiation and nucleolar abnormalities.
Scott C. et al, (2020), Haematologica, Online ahead of print