Beyond H3K4 Methylation: Mechanistic Insights into How KMT2D Controls Transcription, DNA Repair and Genome Stability

About the Project

Details of the Project

KMT2D is one of the most frequently mutated genes in human cancer, with recurrent loss-of-function alterations in lymphoma, bladder, colorectal and gastric tumours, and is the causative gene in Kabuki syndrome. Despite this broad disease relevance, we still lack a fundamental understanding of how KMT2D protects cells from malignant transformation. Increasing evidence suggests that its tumour-suppressive functions extend far beyond its canonical role as an H3K4 methyltransferase at enhancers.

Our previous work showed that loss of KMT2D leads to transcriptional stress, DNA damage and genome instability by impairing RNA polymerase II elongation1. Notably, many cancer-associated mutations truncate or remove the SET catalytic domain yet still promote oncogenesis. This raises a critical mechanistic question: which tumour-suppressor functions of KMT2D require H3K4 methylation, and which arise from non-catalytic activities? Resolving this distinction is essential for understanding both cancer development and the molecular pathology of Kabuki syndrome.

This PhD project will dissect how KMT2D safeguards transcription, DNA repair and genome integrity, using complementary genetic models such as KMT2D-null human cancer cell lines and ΔSET mutants that mimic clinically observed catalytic-domain deletions. You will define how KMT2D regulates transcriptional networks, chromatin architecture, replication-stress responses and DNA repair pathway choice. You will also assess how loss of full-length or catalytic KMT2D influences cellular responses to DNA-damaging chemotherapy, ionising radiation and metabolic inhibitors that perturb transcription.

The project uses a wide methodological toolkit spanning RNA-seq, ChIP-seq, CRISPR, qPCR, chromatin and protein assays, immunofluorescence microscopy, DNA damage/repair, and genome instability assays. Integrative computational analysis of multi-omic datasets will be central to hypothesis generation and mechanistic interpretation.

Co-supervised by experts in transcriptional regulation (Kantidakis) and DNA damage biology (Kysela), this project provides rigorous training in cancer epigenetics, chromatin biology and genome-stability research, with direct relevance to precision oncology and developmental disorders.

Overseas Applicants

Overseas applicants may apply for this studentship but will need to pay the difference between the ‘Home’ and the ‘Overseas’ tuition fees. Currently the difference between ‘Home’ and the ‘Overseas’ tuition fees is £17,712 for 2026/7. As part of the application, you will be required to confirm that you will provide this additional funding. Please indicate this on the application form in the funding section. This project has associated consumables costs which should be discussed with the supervisor in the first instance and before applying. The supervisor can be contacted at t.kantidakis@aston.ac.uk. When applying, please upload copies of your discussions with the supervisor as confirmation.

Location

This position will be based on the Aston Campus in Birmingham, UK. The successful candidate will need to be located within a reasonable distance of the campus, and will be expected to visit in person regularly.

Person Specification

Candidates should have been awarded, or expect to achieve, EITHER:

a] a First or Upper Second Class award in their undergraduate degree, in a relevant subject.

OR

b] a First or Upper Second Class award in their undergraduate degree, and a Merit or Distinction in a Masters degree, both in a relevant subject.

Qualifications from overseas institutions will be considered, but performance must be equivalent to that described above, and the University reserves the right to ascertain this equivalence according to its own criteria.

Contact information

For formal enquiries about this project contact Dr Theo Kantidakis at t.kantidakis@aston.ac.uk

Submitting an application

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. A Curriculum Vitae (Resume) which details your education and work history.
5. Two academic refereeswho 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.
6. 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.
7. 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.

Apply for this position here

Please select “Research - Health Sciences” from the application form options.

If you require further information about the application process please contact the Postgraduate Admissions team at pgr_admissions@aston.ac.uk

Funding Notes

This project covers the Home tuition fees. Candidates who do not have Home status will be responsible for the difference in tuition fees. Currently the difference between ‘Home’ and the ‘Overseas’ tuition fees is £17,712 for 2026/7. This project has associated consumables costs which should be discussed with the supervisor in the first instance and before applying. The supervisor can be contacted at t.kantidakis@aston.ac.uk. When applying, please upload copies of your discussions with the supervisor as confirmation.