CCT/Nehru Memorial Trust studentship: Histone H3 lysine 9 demethylation in cardiac hypertrophy

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Heart disease is a significant cause of mortality in the developed world. In 2004 it was responsible for 137,700 deaths in the UK, equating to 24% of all deaths. A major predictor of mortality due to heart disease is cardiac hypertrophy (an increase in cell size without increase in cell number), and it is the most important risk factor for heart failure in humans. Hypertrophy can however also be a beneficial adaptive response providing the increased blood supply required during pregnancy and to sustain levels of increased physical activity experienced by athletes. Cardiac hypertrophy is characterised by an increase in the muscle mass/size of the heart due to enlargement of heart cells without any proliferation. This increase in heart size is caused by a significant change in the expression levels of a number of genes (the copying of DNA information into RNA and then often into protein) - some are upregulated whereas the expression of other genes is decreased. This remodelling of gene expression is controlled by factors (transcription factors) that bind to the DNA as well as by proteins that modify the structure and packaging of DNA. In genes that are active, the DNA is in an open conformation allowing access to transcription factors that cause the induction of gene expression. To inhibit gene expression, DNA is modified in a way to decrease its accessibility to these transcription factors. In this study, we plan to investigate these mechanisms that control suppression of gene transcription. In particular, the role of enzymes responsible for the de-methylation of the histone proteins around which the DNA is wrapped will be studied. We will also plan to identify how changes in the environment, associated with hypertrophic stress, signal to these histone modifying enzymes to control activity.

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