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Genomics, gene regulation and disease: How human genome variation affects gene expression


Project Description

Epigenetics is often described as mechanisms that maintain gene expression profiles through multiple cell divisions long after the initiating signal has been lost. Aberrant epigenetic changes are now understood to be a driving force in many human cancers. The main interest of the Milne lab is in determining how different epigenetic modifications influence the 3D organization of DNA in the cell resulting in altered transcriptional states. The key approaches used in studying this problem include genome wide computational approaches as well as basic molecular biology and biochemical techniques. We wish to build on these areas with both machine learning and single cell imaging techniques.

All members of the Milne group are trained in both “wet lab” molecular biology and biochemical techniques as well as in bioinformatics. The Milne group also works in close collaboration with several other groups in the WIMM and training in cutting edge CRISPR/Cas9 mediated genome editing techniques and high resolution imaging (see below) is available. In collaboration with the Hughes group, we will generate high quality genome wide maps of normal and leukaemia cells. These datasets will be further interrogated using machine learning approaches to determine how alterations of the epigenetic landscape drive leukaemogenesis. This data analysis will then be combined with a single cell analysis approach. Dynamic imaging techniques such as Single Molecule Tracking (SMT) techniques and fluorescence correlation spectroscopy (FCS) allow quantification and characterization of protein movement within single cells. Collecting data at the resolution of single molecules in single cells provides the possibility of capturing the stochastic nature of gene regulation. Even subtle modifications and effectors of proteins are measurable through the direct or indirect effect these changes have on how a protein of interest moves in a single cell for example. In collaboration with Dominic Waithe (https://www.rdm.ox.ac.uk/people/dominic-waithe) we plan to use compounds or specific mutations to alter the epigenetic landscape of cells in order to analyse the searching and binding activity of key nuclear proteins required for gene regulation. Through careful study of the kinetics, through either measurement of individual protein movements (e.g. SMT) or through population movement kinetics (e.g. FCS) it will be possible to measure these alterations. This will provide several different training opportunities including the use of high resolution microscopes and the analysis of dynamic imaging data.

The WIMM is at the forefront of dynamical and high-resolution imaging techniques, playing host to the Wolfson Imaging Centre. Within this facility, students of the WIMM can expect to be trained to operate and utilize many forms of fluorescence microscopy specific to their imaging needs. The acquisition of images, especially in dynamical imaging, is only the beginning step however, as a large component of the experimental pipeline involves processing and analysis of the data. For this project students will be supported through this process by Dominic Waithe. Dominic is an expert in imaging and analysis techniques of dynamic processes and is also a group leader specializing in image analysis technique development. Dominic will support in the design and analysis of experiments and will assist the student in their development toward a theoretical and practical understanding of the techniques they employ. Students will be provided with an initial project but are also highly encouraged to develop their own independent and unique perspective on their work.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students. We hold an Athena SWAN Silver Award.

Funding Notes

Funding for this project is available through the RDM Scholars Programme or the WIMM Prize Studentship. Both programmes offer funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

Applications must be received, including all relevant supporting materials, by Friday 11th January 2019 at 12 noon (midday).

Please visit our website for more information on how to apply.

References

DOT1L inhibition reveals a distinct class of enhancers dependent on H3K79 methylation. Laura Godfrey, Nicholas T Crump, Ross Thorne, I-Jun Lau, Emmanouela Repapi, Dimitra Dimou, Jelena Telenius, A. Marieke Oudelaar, Damien Downes, Paresh Vyas, Jim R. Hughes, Thomas A. Milne. doi: https://doi.org/10.1101/383489

The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Numata A, Kwok HS, Kawasaki A, Li J, Zhou QL, Kerry J, Benoukraf T, Bararia D, Li F, Ballabio E, Tapia M, Deshpande AJ, Welner RS, Delwel R, Yang H, Milne TA, Taneja R, Tenen DG. Nat Commun. 2018 Apr 24;9(1):1622.

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia. Kerry J, Godfrey L, Repapi E, Tapia M, Blackledge NP, Ma H, Ballabio E, O'Byrne S, Ponthan F, Heidenreich O, Roy A, Roberts I, Konopleva M, Klose RJ, Geng H, Milne TA. Cell Rep. 2017 Jan 10;18(2):482-495.

MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. Godfrey L, Kerry J, Thorne R, Repapi E, Davies JO, Tapia M, Ballabio E, Hughes JR, Geng H, Konopleva M, Milne TA. Exp Hematol. 2017 Mar;47:64-75.

Mouse models of MLL leukemia: recapitulating the human disease. Milne TA. Blood. 2017 Apr 20;129(16):2217-2223.

MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199. Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M, Geng H, Marzo I, Harutyunyan KG, Golfman L, North P, Kerry J, Ballabio E, Chonghaile TN, Gonzalo O, Qiu Y, Jeremias I, Debose L, O'Brien E, Ma H, Zhou P, Jacamo R, Park E, Coombes KR, Zhang N, Thomas DA, O'Brien S, Kantarjian HM, Leverson JD, Kornblau SM, Andreeff M, Müschen M, Zweidler-McKay PA, Mulloy JC, Letai A, Milne TA, Konopleva M. Cell Rep. 2015 Dec 29;13(12):2715-27.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

Research output data provided by the Research Excellence Framework (REF)

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