Multi-omic analysis of Hypoxia-inducible factor (HIF) transcriptional pathway in kidney cancer

Project Overview

Background

Activation of large transcriptional programmes is a common hallmark of many types of cancer. In kidney cancer, mutational inactivation of the VHL tumour suppressor gene directly activates hypoxia-inducible factor (HIF). This transcription factor orchestrates the normal cellular physiological responses to oxygen and activates many hundreds of genes depending upon the cellular context. Whist some of these genes will be driving the cancer, many are neutral bystander genes and some even restrict tumour growth. Our group is exploring the factors that reshape the HIF pathway to promote tumour growth. In particular, we are examining how germ-line variants that pre-dispose to kidney cancer, somatic mutations that are acquired during the pathogenesis of kidney cancer and epigenetic events that re-shape the chromatin structure contribute to this process. This approach will not only provide fundamental insights into the molecular basis of kidney cancer, but will help distinguish driver events from simple bystander events. Furthermore, it will help inform on the importance of tumour hypoxia in other tyopes of solid tumour as well as providing a paradigm for thinking about how other large transcriptional pathways are modified in other cancer types.

Project

The project will use next-generation sequencing techniques such as ChIP-seq RNA-seq, ATAC-seq and Capture-C (chromatin looping) to study the transcriptional responses to HIF in kidney cancer cells and in normal renal tubular cells and to relate it to the chromatin environment. These will be interpreted in the light of other large-scale datasets, including GWAS analyses of germline variants contributing to kidney cancer from collaborators at the NCI, pan-genomic analyses of somatic variants in kidney cancers from The Cancer Genome Atlas (TCGA), and further epigenetic studies from the ENCODE Consortium.

 

The project would suit an enthusiastic student who is interested in combining cutting-edge molecular biology techniques with next generation sequencing and bioinformatic analyses to study effects across the genome. Although the group has its own dedicated bioinformatic support, students will be expected to play a role in the computational analysis of their own data and training will be provided. This is an increasingly important skill in modern biological research that will be increasingly in demand in the job market.

 

Training Opportunities

Molecular and cellular biology. Handling and manipulation of cell-lines. Cloning and re-expression of transgenes using plasmid and viral based vectors. Gene suppression using RNAi and Crispr/CAS9 technologies. Analysis of proteins by Immunoblot. Quantitative (q)PCR analysis of RNA and DNA.

High-throughput sequencing. Training will be provided in preparing samples for next-generation sequencing, including chromatin immunoprecipitation (ChIP-seq), RNA-sequencing, DNAse/MNAse-sequencing, exome-sequencing and Capture-C. Library preparation.

Bioinformatic analysis of sequencing data. Training will be provided in handling many types of large datasets, in particular next-generation sequencing. Analyses will include mutation calling, transcript analysis, calling of ChIP-seq peaks, analysis of chromatin looping and higher level integration of different types of data.

 

The group is based in the Target Discovery Institute on the Old Road Campus, adjacent to the Oxford Genomics Centre, which houses the University's main high-throughput sequencing facility. The Old Road Campus has a major focus on cancer research and is adjacent to the NHS Oxford Cancer Centre, with which we have close links. There are active training and seminar programmes throughout the site. The group is funded by programme grants from the Wellcome Trust, Cancer Research UK, NIHR and the Ludwig Institute for Cancer Research.

Theme

Cancer Biology and Physiology, Cellular & Molecular Biology

Admissions

Project reference number: 1029

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor David R Mole FRCP Target Discovery Institute Oxford University, NDM Research Building GBR david.mole@ndm.ox.ac.uk
Professor Sir Peter J Ratcliffe FRS Target Discovery Institute Oxford University, NDM Research Building GBR peter.ratcliffe@ndm.ox.ac.uk

There are no publications listed for this DPhil project.