Isolation and Characterisation of Histone Deacetylase 9 and its Differentially Expressed Isoforms University of London
Covalent modification of histones by reversible acetylation plays a key role in regulating gene expression. In a number of haematopoietic malignancies, disease pathogenesis has been associated with aberrant recruitment of histone deacetylases (HDACs) by a variety of oncoproteins leading to deregulated gene expression. Consequently, in recent years, the development of HDAC inhibitors for use in anti-cancer therapy has been a focus in clinical oncology research. However, the functional specificities that underpin the roles of various HDACs in oncogenesis are not understood. This thesis describes the isolation and sation of the class II HDAC, histone deacetylase 9, and the results of studies addressing its role in a variety of neoplastic diseases. The HDAC9 gene is highly complex, containing multiple promoters, and gives rise to alternatively spliced transcripts that encode protein isoforms with distinct biological activities. Isoforms of HDAC9 interact differentially with transcriptional repressors and corepressors such as BCL6, TEL and NCoR, display distinct cellular localisation patterns and are targeted by different post-translational modifications. Abnormal patterns of expression of HDAC9 isoforms have been detected in pre-B ALL cell lines and patient samples, including those harbouring the TEL-AML1 rearrangement. In addition, HDAC9 expression appeared to be deregulated in a number of non-haematological tumours, including breast and colon. Consistent with its expression in B cell tumours, HDAC9 protein is found to be expressed in normal spleen B cells, but is primarily confined to the marginal zone and at considerably lower levels than in B cell malignancies. These data might indicate a direct involvement of HDAC9 in some B cell malignancies and solid tumours and reinforce the need to explore a role for combination therapy involving specific HDAC inhibitors.
Biochemistry University of Stirling
My research career has focused on basic and translational research into deregulated epigenetics and differentiation in cancer. I also have a very strong interest in developing strategies to therapeutically target the MYC family oncoproteins. My research career began in the laboratory of Prof Arthur Zelent at the Institute of Cancer Research (ICR) when his major research focus was building on ground-breaking work demonstrating that insensitivity to all-trans-retinoic acid (ATRA) in PLZF-RARα-associated acute promyelocytic leukaemia (APL) compared to ATRA-responsive PML-RARα-associated APL was underpinned by differential recruitment of a histone deacetylase (HDAC)-containing epigenetic complex. During my PhD I demonstrated that aberrant epigenetics in TEL-AML1-associated childhood acute lymphoblastic leukaemia resulted from deregulated recruitment of HDAC epigenetic activity. I went on to identify and characterize histone deacetylase 9 (HDAC9) as the main focus of my PhD. Throughout my career I have sought to better understand the roles of deregulated epigenetics and signalling pathways to guide new therapeutic approaches.
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SCIU3CB - Skills for Cell Biologists The ability to communicate effectively is a highly desirable attribute in bioscience graduates, regardless of the career paths they follow. Furthermore, mastering communication and study skills are essential if undergraduates are to maximise their potential during their degree. Whilst at university, students need to acquire a variety of presentational skills that will typically include individual and group oral and poster presentations, and the writing of essays, practical reports, literature reviews and dissertations. In all these forms of communication, students are required to be able to summarize material while at the same time avoiding plagiarism. In terms of writing, many students (even those who are skilled in written English) can struggle with formal scientific writing. This module aims to provide the student with the skills and confidence to effectively communicate scientific material, as well as practical advice on study and coursework preparation.
BIOU8GF - Genetic Engineering for the Future While humans have been manipulating the genomes of plants and animals through selective breeding for millennia, recent advances in genetic engineering have the potential to revolutionize almost every aspect of our lives. The aim of this module is toprovide students with a comprehensive understsnding the state of the art in genetic engineeringand how these developments are being applied in the clinic,industry andthe laboratory.
BIOU6PL - Applied Biological Sciences Placement This placement module is compulsory for students on the Applied Biological Sciences degree programme. Students on the Cell Biology degree programme may also take this module subject to availability and on a competitive basis. The principle aim of this module is to impart to students an awareness of what work in the life sciences sector entails, and the core skills that are required. Students will gain valuable work experience that will improve confidence and boost their employability skills.
BIOU5EN - Enzymes and their Applications This module aims to provide students with a comprehensive understanding of the properties and functions of enzymes. It also aims to develop team-working as well as practical skills necessary to work with enzymes in the laboratory. The module will cover the following areas: • Protein biochemistry, including secondary, tertiary and quaternary structure.
• Overview of enzymes and their importance.
• Principles of enzymatic catalysis.
• Enzyme mechanisms, parameters affecting enzyme activity and enzyme inhibition.
• Roles of enzymes in key physiological processes.
• Applications of enzymes and their inhibitors in industry and research.