Oxygen is essential for the survival of most organisms. Oxygen supply is also altered in a number of diseases such heart attack, stroke or cancer. My research is focused on understanding how cells sense and respond to reduced oxygen availability, with the aim of improving the outcome of such diseases in patients.
My lab is interested in how cells sense and respond to hypoxia. Hypoxia, or decreased oxygen availability, is an important stimulus for physiological processes such as embryo development but importantly plays a role in the pathology of numerous human diseases. Furthermore, hypoxia is associated with treatment resistance. As such, understanding the mechanisms controlling the cellular responses to hypoxia is of great importance.
In response to hypoxia, cells alter a number of important processes aiming to restore oxygen homeostasis. As such, cells change their transcriptional programme, we hypothesise that chromatin structure changes, translation is modulated, cell cycle is controlled and non-coding RNAs are specifically altered. One of the best known factors controlling the transcriptional programme in hypoxia are the Hypoxia Inducible Factor (HIF) family of transcription factors (HIF-1alpha, HIF-2alpha and HIF-3alpha). Oxygen-mediated control of these transcription factors is achieved by the action of a class of dioxygenases encompassing prolyl-hydroxylases (PHDs) and Factor Inhibiting HIF (FIH), an asparagine hydroxylase. Hydroxylation by PHDs creates a high affinity binding site for the tumour suppressor von Hippel Lindau (VHL), which promotes ubiquitination and rapid proteasomal degradation of HIF-α in normal oxygen tensions. FIH mediated hydroxylation of HIF-α, inhibits binding to co-activators such as CBP/p300, resulting in reduced transcriptional activity.
My research is focused in three of these areas: transcriptional regulation, analysis of chromatin structure changes and cell cycle control in hypoxia. We have identified non-canonical mechanisms controlling HIF levels and activity via a functional interaction with NF-kappaB, Cezanne (OTUD7b, a Lysine 11-ubiquitin specific de-ubiquinase), PITX1 and E2F1. In addition, we have demonstrated that chromatin remodelling complexes are important regulators of the cellular response to hypoxia.
Given that PHDs are the main regulators of HIF, we investigated if PHDs had other functions in the cell. We have found that PHD1 and PHD2 are important regulators of the cell cycle. We have identified the first non-HIF related target for PHD1, in the centrosomal protein Cep192. In addition, we have shown that PHDs themselves are cell cycle regulated. CDK-mediated phosphorylation of PHD1 controls its substrate specificity in cells, without affecting its intrinsic hydroxylase activity.
A multimodal imaging platform with real-time super-resolution for research across the life sciences
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL (BBSRC)
May 2018 - April 2019
The interplay between the oxygen sensors PHDs and the cell cycle
WELLCOME TRUST (UK)
September 2017 - August 2022