Congenital heart disease (CHD) is the most frequent birth defect manifested with various abnormalities in heart development but the underlying aetiology is less known. Genetic and environmental factors are thought to be major contributing factors to the CHD development. Tetralogy of Fallot (TOF) is a common CHD condition characterised by pulmonary stenosis, overriding aorta, ventricular septal defect and right ventricular hypertrophy. To identify the genetic variants underpinning TOF, we have conducted whole exome sequencing of 829 patients samples and identified many deleterious gene variants including a number of missense and loss of function variants in a histone methyl transferase gene called KMT2C. Post-translational methylation of lysine residues on histone tail is a key dynamic chromatin modification and KMT2C mediated H3K4 methyl transferase activity is thought to activate gene enhancers. We have developed a genetically engineered mouse model of Kmt2c lacking its histone methyl transferase activity and demonstrated that the mouse embryos do develop a ventricular septal defect even though with a low penetrance. We also unexpectedly identified a defect in compact myocardium formation reminiscent of a heart condition called left ventricular noncompaction. This project aim further characterise mouse models for the non-compaction phenotype where Kmt2c is genetically engineered globally as well as specifically in cardiomyocytes which will further shed evidence to the molecular pathways responsible for this phenotype. Our recent RNA sequencing data suggest an epigenetic regulation of extracellular matrix proteins mediated by Kmt2c is essential for the formation of compacted myocardium as well as the cardiac trabeculae formation. This project will investigate this hypothesis using various molecular biological as well as bioinformatical tools and validate target candidate genes and its cellular functions during heart development.
https://www.research.manchester.ac.uk/portal/bernard.keavney.html
Entry Requirements
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
How to Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
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