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Investigating the Mechanism of the FeII/2-Oxoglutarate-Dependent Histone Demethylases by a Combined Biochemical/Biophysical Approach

Objective

Histone modifications play important roles in chromatin regulation. Methylation of lysine-residues on histone H3 and H4 affects processes ranging from transcriptional regulation to epigenetic silencing. The recent identification of histone lysine demethylases has clearly demonstrated that histone methylation is not a stable epigenetic mark, as previously assumed. The largest family of demethylases employ 2-oxoglutarate as a co-substrate. Each of these demethylases displays remarkable sequence and methylation-state specificity; however, little is known about the mechanisms by which this selectivity is achieved. For the JMJD2 subfamily of histone demethylases the selectivity for different peptide lengths, sequences and methylation states will be investigated using both biochemical and biophysical approaches. The detailed chemical mechanism of these demethylases will also be investigated using a variety of methods, including EPR, Mössbauer and UV-Visible spectroscopic methods, in combination with more conventional biochemical assays. The oxygen-dependence of these enzymes will also be investigated. Finally, peptide arrays of combinatorially-modified histone peptide fragments will provide insights into the ability of these demethylases to recognise and demethylate multiply-modified histone sequences. Overall, these studies will provide molecular detail on how chromatin is regulated by histone demethylases.

Call for proposal

FP7-PEOPLE-2009-IEF
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Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Address
Wellington Square University Offices
OX1 2JD Oxford
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 173 240,80
Administrative Contact
Linda Pialek (Ms.)