My work focuses on the role of the Ets-related gene ERG in regulating endothelial gene expression and angiogenesis.
Angiogenesis is the growth of new blood vessels and is an important natural process that occurs during wound healing and development. However, abnormal blood vessel growth underlies many diseases, including cancer, age-related blindness, diabetic ulcers, stroke and cardiovascular disease.
Angiogenesis involves the sprouting of endothelial cells from existing blood vessels in a tightly regulated process that requires the integration of signals from growth factors, adhesion molecules and other cellular pathways.
Specialised endothelial tip cells, which are highly motile and extend numerous filopodia, lead the outgrowth of the vessel sprout towards gradients of VEGF.
Transcriptional Regulation of Angiogenesis
Angiogenesis depends on the dynamic regulation of endothelial cell gene expression. There is a complex network of transcriptional regulators that have a fundamental role in regulating the precise temporal and spatial co-ordination of the expression of multiple genes during angiogenesis.
My interest in angiogenesis focuses on the role of the Ets-related gene ERG (a member of the ETS family of transcription factors). Erg is one of the most highly expressed ETS transcription factors in endothelial cells and drives the expression of genes that define the endothelial lineage, including many that are involved in angiogenesis.
We have shown that Erg is required for endothelial monolayer stability, endothelial cell survival and angiogenesis - partly through driving expression of the adhesion molecule VE-cadherin. Birdsey et al (2008) Blood 111(7): 3498-506
To understand in more detail the molecular mechanisms regulating angiogenesis, we make use of a number of techniques including:
- transcriptional biochemistry
- microarray analysis
- computational biology
- confocal immunofluorescence microscopy
- time-lapse microscopy
- in vitro and in vivo models of angiogenesis (e.g postnatal retinal sprouting, co-culture and Matrigel tube formation assays).
Recenlty, we have used these approaches to define a role for Erg in regulating endothelial cell migration, a key process during angiogenesis. Microarray analysis of Erg-deficient endothelial cells identified over 80 genes involved in cell migration as candidate Erg targets, including many regulators of Rho-GTPases. Live cell imaging of Erg-deficient endothelial cells showed decreased migration in a scratch-wound assay, along with a reduction in lamellipodia formation and disruption to the actin and tubulin cytoskeleton.
The regulation of cell migration and cell signalling by Erg has recently featured in an Italian comedy film called "Into Paradiso", directed by Paola Randi. We provided images of migrating cells for the film's opening title sequence.
Transcriptional and epigenetic control of endothelial homeostasis and lineage identity, St George's, University of London, St George's, University of LondonCranmer TerraceLondon SW17 0RE, 2019
Transcriptional and epigenetic control of endothelial homeostasis and lineage identity, King’s College London, King’s College London School of Cardiovascular Medicine & SciencesBHF Centre of Research ExcellenceJames Black Centre125, Coldharbour LaneLondon SE5 9NUUnited Kingdom, 2019
Transcriptional and epigenetic control of endothelial homeostasis, European Society for Microcirculation (ESM) and the European Vascular Biology Organization (EVBO) Summer School, Technische Universitat DresdenDresdenGermany, 2018
The ETS factor ERG controls an endothelial-specific transcriptional regulatory program associated with super-enhancers, NAVBO Vascular Biology 2017, Asilomar Conference Grounds, Monterey, California, USA, 2017
Transcriptional control of angiogenesis, European Society of Cardiology (ESC) Congress 2017, Barcelona, Spain, 2017
Regulation of vascular development and angiogenesis by the ETS transcription factor ERG, University of Wolverhampton, University of WolverhamptonWulfruna StreetWolverhamptonWV1 1LYUK, 2015
Regulation of vascular development and angiogenesis by the ETS transcription factor ERG, Joint Meeting of the European Society for Microcirculation (ESM) and the European Vascular Biology Organization (EVBO)., Pisa, Italy, 2015
The Transcription Factor Erg Regulates Angiogenesis and Endothelial Cell Migration, 4th International Meeting on Angiogenesis, Amsterdam, Netherlands, 2011
26th Meeting London Vascular Biology Forum, Royal Veterinary College, London, 2010
Molecular and Cellular Mechanisms of Angiogenesis, University of Chester, UK, 2009
4th European Meeting on Vascular Biology and Medicine, University of Bristol, 2007