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.
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.
