Mechanisms controlling gene expression in hypoxia and inflammation

Description

Oxygen is one of the most important molecules for life. Every member of the animal kingdom depends on oxygen to help metabolize its food and drive many critical processes in metabolism. Because oxygen is so important most organisms have evolved ways of adapting to changes in oxygen concentration that occur at times of heavy exercise or as individuals migrate to the high levels of altitude. Reduced oxygen availability is best known as hypoxia. To respond to hypoxia, mammalian cells activate a transcriptional programme mediated by Hypoxia Inducible Factors (HIFs). Two main HIFs coordinate this response, HIF-1a and HIF-2a. Oxygen sensing in cells involves critical enzymes known as Dioxygenases, these include enzymes that control the expression and activity of the Hypoxia Inducible Factors (HIFs) (prolyl-hydroxylases and Factor Inhibiting HIF), Histone demethylases, DNA and RNA demethylases. Interestingly, many of these enzymes are under the direct control of HIFs. This indicates that hypoxia can modulate gene expression from chromatin structure, transcription and translation, as well as mRNA decay.

In addition, previous findings from the Rocha laboratory demonstrated that the HIF system also responds to inflammation. This is an evolutionary conserved response, also observed in the model organism Drosophila melanogaster. Specifically, we have demonstrated an intricate crosstalk between HIF and the transcription factor NF-kB (best known for its role in immune responses).

This project aims at investigating the communalities and differences in the cellular response to hypoxia and inflammation. A number of techniques ranging from proteomics, genomics, imaging, biochemistry and molecular and cellular biology will be used.

To apply to this project, email your CV and cover letter to the primary supervisor: Sonia.rocha@liverpool.ac.uk