Mechanistic Insights into How KMT2D Controls Transcription, DNA Repair and Genome Stability
Explore how KMT2D mutations contribute to cancer and developmental disorders by dissecting its role in transcription and DNA repair. Use cutting-edge genomic techniques to differentiate catalytic and non-catalytic tumor-suppressor mechanisms.
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Project Description
Project Overview
KMT2D is a frequently mutated gene in various cancers and the causative gene in Kabuki syndrome. Despite its importance, the mechanisms through which KMT2D protects cells from malignant transformation remain unclear. This project aims to dissect KMT2D's roles in transcription, DNA repair, and genome stability, focusing on both catalytic and non-catalytic tumor-suppressor functions.
What You Will Do
You will use genetic models including KMT2D-null human cancer cell lines and ΔSET mutants to study transcriptional networks, chromatin architecture, replication-stress responses, and DNA repair pathway choice. The project employs methods such as RNA-seq, ChIP-seq, CRISPR, qPCR, chromatin/protein assays, immunofluorescence microscopy, and genome instability assays. Integrative computational analysis will be central to the research.
Expected Outcomes
The project is expected to clarify which functions of KMT2D depend on H3K4 methylation and which arise from non-catalytic activities. It will also reveal how loss of KMT2D affects cellular responses to DNA-damaging chemotherapy and ionising radiation, advancing understanding of cancer development and Kabuki syndrome molecular pathology.
Why This Matters
Understanding KMT2D's multifaceted roles could inform precision oncology strategies and provide new insights into developmental disorders like Kabuki syndrome. The findings will advance epigenetics, chromatin biology, and genome stability research, relevant to cancer biology and therapeutic development.
Entry Requirements
How to Apply
Eligibility
Supervisor Profile
Dr. Theo Kantidakis specializes in transcriptional regulation and epigenetic mechanisms underlying cancer biology. His research focuses on how chromatin modifications influence RNA polymerase II elongation and genome stability. He collaborates with expertise in DNA damage biology to investigate molecular pathways relevant to cancer and genetic disorders.