Home| Professor of Human Genetics |
Contact details:
| Tel: | +44 20 7882 2595 |
| Fax: | +44 20 7882 2180 |
| Email: | d.sheer@qmul.ac.uk |
| Address: | Centre for Neuroscience and Trauma, |
Biography
After completing a B.Sc (Hons) in Embryology and Zoology at the University of the Witwatersrand, Johannesburg in 1973, I ran a diagnostic genetics laboratory at the South African Institute of Medical Research for two years. I then moved to the University of Oxford , where I was awarded a D.Phil. in 1980. Following a Post-Doctoral Research Fellowship at the Imperial Cancer Research Fund (now the Cancer Research UK London Research Institute), I became Head of the Human Cytogenetics Laboratory in 1983, where I conducted research on genome biology and cancer genetics. I moved with my group to the Blizard Institute of Cell and Molecular Science in November 2006.
Research Activity
A major aim of our research is to understand the structural and functional organisation of the human genome and the nucleus. Chromatin is packaged by a hierarchical series of folds into individual chromosome territories. While the first level of packaging, the nucleosomal fibre, is well characterised, little is known about higher order chromatin structure. We are using the Major Histocompatibility Complex (MHC) to understand the principles that govern higher order chromatin architecture and determine its significance for genome regulation. The MHC is the most important genomic region with respect to immunity to infectious agents, autoimmunity and transplantation. We have shown that transcriptional activation of the MHC by IFN-gamma is preceded by massive remodelling of the chromatin fibre, which manifests as a looping out from the chromosome 6 territory. A range of approaches are being taken to understand the mechanism and significance of this chromatin remodelling, including ChIP studies of DNA-protein interactions and epigenetic modifications, and high resolution FISH analysis to delineate chromatin loops.
Chromosome territories are interspersed with a variety of non-chromatin domains such as Cajal bodies and PML nuclear bodies. A central question regarding this organisation is how the activities of the genome and non-chromatin domains are coordinated to regulate nuclear processes. PML nuclear bodies pose a particular challenge, since they contain over 30 different proteins that are involved in a wide variety of nuclear activities. We recently found that PML bodies are closely associated with gene-rich, transcriptionally active genomic regions such as the MHC. We would thus like to understand the significance of this nuclear arrangement and determine how it is maintained from one cell cycle to the next.
We also have a major interest in the contribution of genetic aberrations to tumorigenesis, and in applying genomics to clinical practice. While working with the UK Children's Cancer Study Group (now called the Children's Cancer and Leukaemia Group), we characterised diagnostic and prognostic genetic changes in paediatric small round cell tumours. In a study of progression in breast carcinomas, genomic profiling led us to conclude that most grade III tumours arise de novo rather than by dedifferentiation from grade I tumours. We are currently examining genetic and epigenetic chages in human brain tumours. Our study of the highly aggressive grade IV astrocytoma, glioblastoma multiforme, using array comparative genomic hybridisation, identified novel recurrent aberrations which we are investigating in more detail. We are also analysing aberrations in a large series of paediatric low grade astrocytomas. The data obtained will be compared with clinical and pathological parameters to allow improved tumour classification and a greater understanding of astrocytoma pathogenesis.
Our research is funded by Cancer Research UK and the Samantha Dickson Brain Tumour Trust.
Key Publications
• Volpi EV, Chevret E, Jones T, Vatcheva R, Williamson J, Beck S, Campbell RD, Goldsworthy M, Powis SH, Ragoussis J, Trowsdale J, Sheer D. (2000) Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response response to interferon in interphase nuclei. Journal of Cell Science 113:1565-1576.
• Shiels C, Islam SA, Vatcheva R, Sasieni P, Sternberg MJE, Freemont PS, Sheer D. (2001) PML bodies associate with the MHC gene cluster. Journal of Cell Science 114 (20): 3705-3716.
• Williams RRE, Broad S, Sheer D, Ragoussis J. (2002) Sub-chromosomal positioning of the epidermal differentiation complex (EDC) in keratinocyte and lymphoblast interphase nuclei. Experimental Cell Research 272:163-175
• Donev R, Horton R, Beck S, Doneva T, Vatcheva R, Bowen WR, Sheer D. (2003) Recruitment of heterogeneous nuclear ribonucleoprotein A1 in vivo to the LMP/TAP region of the Major Histocompatibility Complex. Journal of Biological Chemistry 278(7):5214-26
• Wang J, Shiels C, Sasieni P, Wu PJ, Islam SA, Freemont PS, Sheer D. (2004) Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions. Journal of Cell Biology 164(4):515-526.
• Mulholland PJ, Fiegler H, Mazzanti C, Gorman P, Sasieni P, Adams J, Jones TA, Babbage JW, Vatcheva R, Ichimura K, East P, Poullikas C, Collins VP, Carter NP, Tomlinson IPM, Sheer D. (2006) Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme. Cell Cycle 5(7):783-791.
• Donev R, Newall A, Thome J, Sheer D. (2007) A role for Sc35 and hnRNPA1 in the determination of Amyloid Precursor Protein isoforms. Molecular Psychiatry 12(7): 681-690.
• Christova R, Jones T, Wu P-J, Bolzer A, Costa-Pereira AP, Watling D, Kerr IM and Sheer D. (2007) P-STAT1 mediates higher-order chromatin remodelling of the human Major Histocompatibility Complex in response to IFN- g . Journal of Cell Science 20(18):3262-3270.
• Ottaviani D, Lever E, Takousis P, Sheer D. (2008) Anchoring the genome. Genome Biology 9(1):201.
• Ottaviani D, Lever E, Mitter R, Jones T, Forshew T, Christova R, Tomazou, Rakyan VK, Krawetz SA, Platts AE, Segarane B, Beck S, Sheer D (2008) Reconfiguration of genomic anchors upon transcriptional activation of the human MHC. Genome Research 18: 1778-1786.
• Forshew T, Tatevossian RG, Lawson AR, Ma J, Neale G, Ogunkolade BW, Jones TA, Aarum J, Dalton J, Bailey S, Chaplin T, Carter RL, Gajjar A, Broniscer A, Young BD, Ellison DW, Sheer D (2009) Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. 218(2):172-81.
• Lever E, Sheer D (2010) The role of nuclear organization in cancer. J Pathol 220 (2):114-125
• Tatevossian RG, Lawson AR, Forshew T, Hindley GF, Ellison DW, Sheer D (2010) MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol. 222(3):509-14.
• Lawson AR, Tatevossian RG, Phipps KP, Picker SR, Michalski A, Sheer D, Jacques TS, Forshew T. (2010) RAF gene fusions are specific to pilocytic astrocytoma in a broad paediatric brain tumour cohort. Acta Neuropathol. 120, 271-273.
