We are offering a 2 year Career Development Fellowship (CDF) which is a training and development position for post-doctoral scientists. Applicants will have recently completed their doctoral studies.
Project Title : The liver epigenome and its response to Non Genotoxic Carcinogen (NGC) exposure.
The aim of the MARCAR project is to identify early biological indicators ("biomarkers") that can be used to predict the effects of Non Genotoxic Carcinogen (NGC) exposure. These compounds are not cancerous directly, i.e. not genotoxic. Instead they perturb metabolic processes such as increased cell division that predispose to cellular transformation. Drugs that induce such cancers are NGC’s. A principle aim of the project is to identify early biological indicators (biomarkers) that can be used to predict the effects of NGC exposure. The liver is the major target organ for such drug-induced tumours and the MARCAR project aims to develop early markers of this carcinogenic risk.
The conversion of normal cells into cancer typically involves several steps resulting in the acquisition of unlimited growth potential (immortality). Both genetic and epigenetic changes have been detected in a number of different cancer cell types. Epigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. Generally, these changes lead to the activation of oncogenes and the inactivation of tumour suppressor and pro-apoptotic genes. A number of tumour suppressor genes have been shown to be silenced by promoter DNA methylation, where and how epigenetic alterations cooperate with genetic changes during the transformation process is of great interest.
We want to elucidate if DNA modification (5-methylcytosine and 5-hydroxymethylcytosine) patterns are altered in liver after short term exposure to Non Genotoxic Carcinogens (NGC) and if these predispose to cellular transformation. We will utilize DNA methylation and 5-hydroxymethylation enrichment techniques coupled with array technologies to determine their genome wide patterns in normal and treated rodent livers that will be provided by consortium partners. This will be a collaborative high-throughput project that will at the same time address basic biological processes. The attachment of a methyl group to cytosine (and subsequent hydroxylation) is an ancient mechanism that influences use and storage of genetic information. The process of DNA methylation is regulated by cytosine specific methyltransferases that establish or maintain methylation patterns at defined genomic regions and by demethylation functions that control general or target-specific removal of methylation. DNA modification plays a crucial role in gene regulation and in determining the competence of a gene to be expressed. Many genes contain methylation-free regions that favour their activity, while others are marked by DNA methylation in certain cell types to restrict their activity. Cancer development is often associated with mistakes in DNA methylation patterns inhibiting expression of essential genes or facilitating expression of detrimental genes. Among animals and plants, some enzymatic and targeting characteristics have been evolutionary preserved while others have diversified. A functional analysis of liver-specific DNA methylation functions will define how common and dynamic DNA methylation functions are. This will improve our understanding of target specificity and interplay between DNA methylation functions and toxic compound exposure.