- Baker Medical Research Institute, Melbourne, Australia
Understanding the MeCP2-associated regulatory complex in disease
Alterations in the controls of DNA methylation and histone deacetylation play a profound role in human disease. We are interested in examining epigenetic events such as DNA methylation, histone modification and the determinants involved on chromatin to further our understanding of endogenous gene transcription. These studies are now challenging the way we view gene regulation beyond our simple understanding of "textbook" operations. Our desire to dissect the molecular details allows us to determine the roles of transcriptional regulators and provide us with a greater understanding of how they are involved in transcriptional regulation.
Improving molecular targeting and treatments for cancer gene therapy
This Hons and PhD Program will investigate the effect of HDACi on radiation-induced DSB repair in transcriptionally active or inactive euchromatin and constitutive heterochromatin analyses of γH2AX accumulation and hyperacetylation of histone H3 using chromatin immunoprecipitation (ChIP). The candidate will investigate pre-treatment with low concentration of HDACi before irradiation, results in classic hallmarks such as histone hyperacetylation and the stable accumulation of γH2AX that is more pronounced in euchromatic alleles than heterochromatic areas of the genome. At this exciting stage of gene therapy, our combined results suggest that the inhibition of HDACs can potentiate therapy by a mechanism that renders DNA more accessible to treatments by histone hyperacetylation in the absence of cytostasis, apoptosis and/or growth arrest in mammalian cells.
Identification of new regulatory mechanism of transcriptional repression in response to cancer chemotherapy
The general focus of this project is to investigate the mechanisms by which specific MBD1 regulatory complexes serve to integrate and repress gene in models of cancer. Specifically, the project will define the functional roles of specific components of the co-repressor complexes in gene repression events and characterise the link to cancer-associated loci such as the multidrug resistance gene (MDR1) using genetic and genomic approaches. The central focus of this aim takes the Teams latest findings on transcriptional repression to the next logical step and further extends the mechanism, as currently understand and published recently in Nature Genetics (2005) 37:254-264 and Oncogene (2005) 24:8061-7075. The project is aimed to examine the controversial point of MBD1 repression independent of direct DNA methylation.
Set7 histone methyltransferase regulating gene activation in response to cancer chemotherapy
The general focus of this project is to define the roles of the histone methyltransferase Set7 and other associated complexes in gene activation events central to gene deregulation in cancer models using biochemical and genomic approaches.
To our knowledge, these exciting findings present a new paradigm for Set7 function. These novel findings in this area not only provide us with a greater understanding of transcriptional control in cancer disease but also at a more general level.
Genetic memory in diabetes
This Hons and PhD Program will investigate the epigenetic pathways that act as a bridge linking hyperglycaemia to the central molecular and cellular events, which lead to vascular injury in diabetes. We have identified that in the context of a hyperglycaemic milieu, transcriptional competence is directly linked with epigenetic changes. These findings present a new paradigm for histone methyltransferase function and epigenetic modification that is relevant to our understanding of the transcriptional response to glucose. Finally, these findings will provide new targets for generating end-organ protective agents for the common and devastating clinical problems of diabetic vascular complications.
Heart disease, Stem cells and Epigenetics
This project is designed to address a key issue regarding how pathological stimuli is finally converted into altered gene expression profile that eventually leads to hypertrophy and heart failure. A better understanding on the epigenetic factors in controlling gene transcription in the compromised heart will advance the current knowledge of the mechanism responsible for molecular remodeling in the hypertrophic and failing heart. The planned studies will generate valuable data addressing key questions, including whether modulating genomic methylation can alter hypertrophic growth, whether different gene expression profiles in senescent or hypertrophic hearts could be partly attributable to epigenetic mechanism. Furthermore, these studies could indicate the potential of novel therapeutic targets aimed on epigenetic factors thereby modulating the epigenetic factors to alter or reverse unwanted gene transcription.
Molecular mechanisms of genetic changes in imprinting discorders
Epigenetics is a crucial mechanism in regulating gene expression and epigenetic errors that alter chromatin structure result in various diseases. Genomic imprinting is a specific example of the epigenetic phenomenon whereby gene expression is restricted to only one parental allele. To achieve allele-specific expression, imprinted loci are regulated by epigenetic modifications that mark the parental alleles as either active or repressed. These epigenetic modifications include differential DNA methylation and modifications on the histone proteins. The epigenetic "life cycle" of imprinting is a multistep process (germline erasure, germline establishment, somatic maintenance) involving several components [DNA methyltransferases (DNMTs), histone modifying proteins, methyl CpG binding domain proteins (MBDs), insulator proteins and chromatin-modifying complexes].
Contact: Sam El-Osta
More Information: Full descriptions of PhD projects available
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