ESR (Early Stage Researcher) position for 36 months at Medical Research Council Cancer Unit, University of Cambridge, Cambridge, UK
The Frezza laboratory focuses on understanding the role of the mitochondrial enzyme and component of the tricarboxylic acid (TCA) cycle Fumarate Hydratase in tumorigenesis. We have recently demonstrated that fumarate, accumulated in FH-deficient cells, elicits a powerful epigenetic reprogramming that leads to the suppression of miRNA200, and induction of epithelial¿to-mesenchymal transition (Sciacovelli et al, Nature 2016). This epigenetic and phenotypic switch makes FH-deficient cells more motile and invasive, predisposing to metastasis. Although we demonstrated that fumarate has a role as epigenetic modifier, its effects on chromatin structure and function are still unknown. This project will help to elucidate the link between TCA cycle dysfunction, accumulation of fumarate, and downstream epigenetic changes involved in tumorigenesis. To this aim the ESR will investigate the hypothesis that fumarate controls the activity of histone and DNA demethylases involved in DNA and histone methylation, causing broad epigenetic changes. The ESR will first generate a 3D cellular model of FH-deficiency by deleting FH in human renal cell lines obtained using CRISPR technology. He/she will then perform comprehensive subcellular metabolomics analyses to study the metabolic changes induced by the loss of FH in a compartment-specific manner, focusing in particular on the accumulation of fumarate in the nucleus. Then, the ESR will perform an extensive epigenetic analysis aimed at understanding how fumarate modulates genes expression and chromatin structure by altering DNA methylation and histone marks deposition. To assess DNA methylation, genome scale bisulfite sequencing and liquid chromatography analyses will be performed. Further, ESR will also perform Chip-bisulfite sequencing analyses to evaluate changes in histones binding to chromatin and their association to methylated DNA. These epigenetic changes will be merged with RNA-seq experiments to find the link between epigenetic modification and gene expression.
PhD program starting date: 01/10/2017
Required Educational Level
Degree: Applicants should hold a Masters level Degree in Biological Sciences in the field of Biochemistry, Cell Biology, Cancer Biology.
Skills: The ideal candidate should be familiar with the field of cancer metabolism and have a clear understanding of cellular metabolism and mitochondrial physiology. He/she will have proven experience with cell culture and several lab techniques, including western blotting, molecular biology. The ideal candidate should also be familiar with the basics bioinformatics tools and be familiar with software for data analysis. A distinct advantage will be previous experience with metabolomics experiments and work in the field of caner metabolism, and familiarity with epigenetics.
Additional requirements: Team spirit, good communication skills, and trans-national mobility
Eligibility: The applicants must be in possession of a degree in Biological sciences at the date of recruitment - an 'early stage researcher' (i.e. in the first four years of his/her research career and not have a doctoral degree). The applicants must not have resided in the country where the research training activities take place for more than 12 months in the 3 years immediately prior to the recruitment date and not have carried out their main activity (work, studies, etc.) in that country.
The applicant may be a national of a Member State, of an Associated Country or of any other Third Country.
Please see the below 'Additional Information' document for more details on the vacancy.
Applications, in English, should include a CV, a covering letter, detailed academic transcripts, a copy of the master's thesis and a letter of reference - all to be submitted by email to Christine Fox (cf208@MRC-CU.cam.ac.uk)
The closing date for applications is 30th April 17. The date of interviews is TBC.
Please quote reference SK11707 on your application and in any correspondence about this vacancy.
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