Novel functions of the epigenetic cancer driver KMT2D

KMT2D, previously also known as MLL2 in humans, is a histone 3 lysine 4 (H3K4) methyltransferase. It has attracted attention as it is within the top 10 most mutated genes in cancer genomes, as well as the main reason behind the congenital disorder Kabuki syndrome. Importantly, in contrast to other cancer genes, the functions of KMT2D have not been clearly established yet. It is believed that KMT2D works through methylating H3K4 in chromatin, a mark of active transcription, and facilitating enhancer mediated transcriptional activation. 

We were the first to show that defective KMT2D can contribute to carcinogenesis through DNA damage at the gene loci1. More specifically, we showed that KMT2D interacts with RNA polymerase II at genes and facilitates transcriptional elongation. Inactivation of KMT2D results in DNA damage, transcriptional stress and genomic instability1.

We now plan to investigate the cellular functions of KMT2D in more detail and identify novel ones that are potentially independent of its methyltransferase activity. To this end, we will use  immortalised mouse embryonic fibroblasts (MEF) that are inducible KMT2D knock-outs (KO), as well as human colon cancer HCT116 cells that are stable KMT2D KO or only lack the methyltransferase domain of the protein ( ΔSET)1. 

We will employ a broad range of standard and cutting edge cellular, molecular, biochemical and bioinformatic techniques to examine, for example, how ionising radiation, chemotherapeutic DNA damage agents and metabolic inhibitors affect cellular functions in mouse and human cells lacking KMT2D or its SET domain. These include, among others, RNA-Seq and qPCRs, protein and chromatin assays, immunofluorescence microscopy, DNA damage and repair, and genomic instability assays1.

The Kantidakis lab is a research-active lab, suitable for enthusiastic and highly motivated PhD candidates. The successful candidate will benefit from working alongside the principal investigator, who will provide direct mentorship and training.

References
1.    Kantidakis, T., Saponaro, M., Mitter, R., Horswell, S., Kranz, A., Boeing, S., Aygün, O., Kelly, G.P., Matthews, N., Stewart, A., et al. (2016). Mutation of cancer driver MLL2 results in transcription stress and genome instability. Genes Dev 30, 408–420. 10.1101/gad.275453.115.

PhD programmes are for those who are seeking to develop greater in-depth knowledge in a specific area. Completing this level of study is about making an original contribution to knowledge, making new discoveries and developing lifelong skills. 

At Aston University, our Engineering and Physical Sciences PhD programmes will provide all the support and facilities you will need to develop into a leading researcher in your chosen field.  You will be welcomed into a supportive community with a shared enthusiasm for original research, where diversity and multidisciplinary is championed.

For formal enquiries about this project contact:

Dr Theo Kantidakis

Dr Boris Kysela

Candidates should have been awarded, or expect to achieve, EITHER:
•    A Bachelors degree in a relevant subject with an award of First Class or 2.1. 
OR 
•    A Bachelors degree in a relevant subject with an award of First Class or 2.1, and a Masters degree in a relevant subject with an award of Merit or higher.
Qualifications from other countries which are considered by Aston University to be equivalent to that described above will be eligible to apply.

Essential criteria:
•    Good Coding Skill and willing to evolve them along the journey. 
•    Basics on IP networking
 

We can only consider applications that are complete and have all supporting documents. Applications that do not provide all the relevant documents will be automatically rejected. Your application must include: 

1. English language copies of the transcripts and certificates for all your higher education degrees, including any Bachelor degrees.
    
2. A Research Statement detailing your understanding of the research area, how you would approach the project, and a brief review of relevant literature. Be sure to use the title of the research project you are applying for. There is no set format or word count. 
    
3. A personal statement which outlines any further information which you think is relevant to your application, such as your personal suitability for research, career aspirations, possible future research interests, and further description of relevant employment experience. 
    
4. Two academic referees who can discuss your suitability for independent research. References must be on headed paper, signed and dated no more than 2 years old. At least one reference should be from your most recent University. You can submit your references at a later date if necessary. 
    
5. Evidence that you meet the English Language requirements. If you do not currently meet the language requirements, you can submit this at a later stage. 
    
6. A copy of your passport. Where relevant, include evidence of settled or pre-settled status.

Interviews

Interviews will be conducted online via Microsoft Teams. If you are shortlisted, you will be contacted directly with details of the interview.  

Contact information

For formal enquiries about this project, contact Dr David Benton

Studying a PhD is great route into academia and industries that are centred on research and innovation. Areas with a demand for very high level and specialised research skills often demand PhDs.

In addition to this specialist knowledge, PhD education will help you to develop a set of valuable transferrable skills. The very nature of studying an intensive research degree will enable you to become a team player, develop problem-solving skills, analytical thinking, and advanced presentation and communication skills.

The variety of PhD project topics at Aston means that the destinations of our graduates vary substantially. Some choose to continue into academia, at either Aston or other leading institutions, while others go onto use their newly acquired skills in a range of research, healthcare, industry or charitable fields. When selecting your chosen PhD path at Aston, your supervisor will be able to provide you with relevant career opportunities that could be available to you in your specialist area.