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Epigenetics and Gene Regulation in Leukaemia


Weatherall Institute of Molecular Medicine

Prof T Milne Friday, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

The most common childhood cancer is acute lymphoblastic leukaemia (ALL). There has been amazing progress in treating childhood ALL, but unfortunately a subset of childhood ALL continues to be refractory to treatment. In addition, even for children who are cured, conventional therapies are often quite toxic and can cause long lasting life-altering effects. In the Milne lab, we are trying to better understand how normal gene regulation is disrupted in childhood ALL so that we can better design targeted therapies. Recent work in our lab has focused on a subset of childhood ALL that is caused by rearrangements of the Mixed Lineage Leukaemia (MLL) gene, which create MLL fusion proteins (MLL-FPs). MLL-FPs can directly alter gene expression in the cell through aberrant epigenetic regulation of genes. Work in the lab mainly focuses on gene regulation, specifically using genome wide techniques such as RNA-seq, ATAC-seq, ChIP-seq and 3C techniques to analyse the 3D genome.

Heterogeneity is a major problem for cancer therapy as even patients with the same driver mutations may respond quite differently to treatment. Even with the new breed of highly promising targeted therapies, there is a wide range of patient response that is often difficult to predict for any particular individual. There is much we do not understand about the molecular mechanisms underpinning this heterogeneity, but at least some of it is reflected in differential gene expression patterns between individual patients.
Enhancers are key regulatory elements that contribute to gene expression. They function in part by acting as docking sites for transcription factors, which can then activate appropriate target genes over long distances through mechanisms which have not been fully elucidated. Aberrant enhancer activity is a driving factor in many cancers, and this is a major area of study in the lab. There are two main approaches that would be available to a PhD student. 1) Better understanding how chromatin complexes impact gene expression, especially through the activity of enhancers and 2) better understanding how childhood leukaemias are initiated and how stochastic alterations in local epigenetic environments can also provide the opportunity for the emergence of novel and/or cryptic enhancers, thus contributing to patient heterogeneity.

Interdisciplinary by design, this project will involve interactions with multiple labs in the WIMM and will use a broad range of cutting-edge technologies. This includes state of the art techniques for the analysis of gene regulation on a genome-wide level (ATAC-seq, ChIP-seq, Capture C, nascent RNA-seq), advanced molecular biology, genome editing (e.g. CRISPR/CAS9), as well as computational biology. Training will be specifically provided in the use of basic bioinformatics pipelines, as well as more substantial opportunities for learning bioinformatics. In collaboration with other labs, novel childhood leukaemia models are available for study.

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship and the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.

References

Harman, J. et al., bioRxiv, 2020 https://doi.org/10.1101/2020.06.30.179796

Godfrey, L., et al., Leukemia, 2020. https://pubmed.ncbi.nlm.nih.gov/32242051/

Crump, N. et al., bioRxiv, 2019. https://doi.org/10.1101/848325

Godfrey, L., et al., Nat Commun, 2019. https://pubmed.ncbi.nlm.nih.gov/31243293/

Kerry, J., et al., Cell Rep, 2017. https://pubmed.ncbi.nlm.nih.gov/28076791/

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