Professor Denise Sheer, BSc, BSc(Hons), D.Phil.
Professor of Human Genetics
Website: Researcher ID - Sheer
After completing a B.Sc (Hons) in Embryology and Zoology at the University of the Witwatersrand, Johannesburg, Denise Sheer ran a diagnostic cytogenetics laboratory at the South African Institute of Medical Research for two years. She then moved to the Genetics Laboratory at the University of Oxford, where she was awarded a D.Phil. in 1980. After a Post-Doctoral Research Fellowship at the Imperial Cancer Research Fund (now the Cancer Research UK London Research Institute), she became Head of the Human Cytogenetics Laboratory, where she identified significant genetic aberrations in many malignancies and made critical discoveries on chromosome architecture. She moved with her group to the Blizard Institute in 2006.
Member of The Children’s Cancer and Leukaemia Group
Member of the British Neuro-Oncology Society
Jeremy Jass Prize for Excellence in Pathology – awarded for the discovery of RAF gene fusions in children’s brain tumours (Forshew, Tatevossian et al, 2009)
Professor Sheer has expertise in:
• Higher order chromatin architecture
• Nuclear organisation
• Cell and molecular biology
• Cancer genetics and epigenetics
• Molecular pathology of paediatric brain tumours
MBBS: Lectures, PBLs, Mentoring
Intercalated BSc in Neuroscience: Lectures and project supervision
MSc in Translational Neuroscience: Module Lead for Neuro-Oncology
Brain tumours, cancer genetics; cancer epigenetics; human genetics; genome structure and function; nuclear organization.
Recent and ongoing research projects
Our research is currently based on two inter-related themes: the structure and function of the genome, and the molecular pathology of paediatric brain tumours.
Higher order chromatin architecture
It is crucial to understand how the genetic information is assembled, accessed and interpreted during the processes of development, cellular responses to the environment, and disease. Professor Sheer’s group addresses this question by studying the relationship between the linear and 3D organisation of the genome and transcriptional regulation. Two human model systems are being studied: transcriptional upregulation of the Major Histocompatibility Complex (MHC) on chromosome 6 by Interferon-Gamma, and genome-wide changes during neural differentiation. A breakthrough was made in the field when the group showed a direct link between higher order chromatin architecture and gene expression (Volpi et al, 2000; Williams et al, 2002). This discovery was followed by identification of the signalling pathway leading to changes in chromatin architecture in the MHC and mapping of sites where chromatin becomes reconfigured (e.g. Christova et al, 2007; Ottaviani et al, 2008a,b). Current studies include analysis of early DNA-protein interactions, epigenetic modifications and other chromatin changes that play a role in regulation of transcription in the MHC in response to Interferon-Gamma. In the neural differentiation system, the group is examining the global chromatin modifications and epigenetic changes, and correlating the changes with expression alterations over the first 6 days of neural induction. Other studies in the group include investigations into the role of CTCF and its paralogue, BORIS (CTCFL), in regulation of gene expression (Jones, Ogunkolade et al, 2011)
Paediatric brain tumours
Although low grade astrocytoma is the most common type of children’s brain tumour, relatively few studies have been undertaken to understand how they arise and what determines their clinical behaviour. Our poor understanding of their molecular pathology has hampered efforts to develop effective treatment for these tumours. Professor Sheer‘s group is conducting a detailed analysis of the genetic and epigenetic changes in children’s low grade astrocytomas, in collaboration with Professor David Ellison, St Jude Children’s Research Hospital, Memphis, USA. Her group recently made the crucial discovery of RAF gene fusions that activate the MAPK pathway in virtually every pilocytic astrocytoma (Forshew, Tatevossian et al, 2009; Tatevossian et al, 2010a), which won the Jeremy Jass Prize for Excellence in Pathology. This study and others opened the way for the development of new forms of therapy for children with low grade astrocytoma using MAPK inhibitors (for example, see http://clinicaltrials.gov/ct2/show/NCT01089101). To determine how the RAF gene fusions arise, Professor Sheer’s group then found significant enrichment of sequence microhomology at the breakpoints, which provided insights into the probable mechanisms that give rise to these key genetic abnormalities (Lawson, Hindley et al, 2011). Other investigations of the group have led to the novel finding of MYB gene abnormalities in subsets of low grade astrocytomas (Tatevossian et al, 2010b). Ongoing studies include exome sequencing and epigenetic profiling of paediatric low grade astrocytomas. All the findings will be integrated to give a detailed picture of the molecular basis of brain cancer behaviour, enable early identification of especially aggressive cancers, and identify new targets for treatments to improve the outlook for children with brain cancer.
Jones TA, Ogunkolade BW, Szary J, Aarum J, Mumin MA, Patel S, Pieri CA, Sheer D (2011) Widespread expression of BORIS/CTCFL in normal and cancer cells. PLoS ONE 6(7):e22399.
Lawson AR, Hindley GF, Forshew T, Tatevossian RG, Jamie GA, Kelly GP, Neale GA, Ma J, Jones TA, Ellison DW, Sheer D. (2011) RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology. Genome Research 21(4):505-14.
Tatevossian RG, Lawson AR, Forshew T, Hindley GF, Ellison DW, Sheer D. (2010a) MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol 222(3): 509-14.
Tatevossian RG, Tang B, Dalton J, Forshew T, Lawson AR, Ma J, Neale G, Shurtleff SA, Bailey S, Gajjar A, Baker SJ Sheer D, Ellison DW (2010) MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathol;120(6):731-43.
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.
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.
Christova R, Jones TA, Bolzer A, Wu PJ, Costa-Pereira AP, Watling D, Kerr IM, Sheer D. (2007) P-STAT1 mediates higher order chromatin remodelling of the human Major Histocompatibility Complex in response to IFN-. J Cell Sci 20(18):3262-3270.
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. J Cell Biol. 164(4):515-526.
Shiels C, Islam SA, Vatcheva R, Sasieni P, Sternberg MJE, Freemont PS, Sheer D. (2001) PML bodies associate with the MHC gene cluster. J Cell Sci. 114 (20): 3705-3716.
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 to interferon in interphase nuclei. J Cell Sci. 113:1565-1576.
Roylance R, Gorman P, Harris W, Liebmann R, Barnes D, Hanby A, Sheer D. (1999) Comparative genomic hybridization of breast tumors stratified by histological grade reveals new insights into the biological progression of breast cancer. Cancer Res 59:1433-6.
View all Denise Sheer's Research Publications at: http://www.researchpublications.qmul.ac.uk