I completed my PhD in the laboratory of David Porteous at the MRC Human Genetics Unit in Edinburgh in 1988 and from there moved to Oxford to work in the laboratory of Kay Davies within the institute of Molecular Medicine at the John Radcliffe Hospital. During this period I spent time working in as a visiting PI in the laboratoryof Charles Laird (FHCRC, Seattle, USA) and as a visiting researcher in the laboratory of Alan Wolffe (NIH, Bethesda, USA). I moved to the Open University in 1999 and became a fellow of the Royal Society of Biology in 2017.
Current University Role
Senior Lecturer in Human Genetics
Member of University GM Safety Committee
Royal Soeciety of Biology, Genetics Society (UK), American Society of Human Genetics, the British Society of Genomic Medicine, The Clinical Molecular Genetics Society and the American Association for the Advancement of Science.
Other Activities (present and past)
I currently act as a Scientific Advisor to the UK Fragile X Society, a family support group serving the needs of fragile X families within the UK. This involves writing synopses of research papers in lay-terms, advising the Society on recent research progress and on advances leading to clinical trials, both pharamacological and in the area of gene therapy.
Selection of previous roles:
My post-doctoral research focused primarily on triplet repeat instability, working on both human Fragile X syndrome and its genetics and Huntington’s disease. I developed a major collaborative study at the Open University examining the expansion of the CAG triplet array that underlies Huntington’s disease. This project was based upon a novel variant of the R6-1 mouse model for HD created by Dr Gill Bates. During routine colony screening, a novel CAG truncation event occurred allowing the isolation of a new line of animals carrying a significantly shorter CAG length and a noticeably later onset of ‘disease’ features, allowing an extended window into some of the early events associated with CAG expansion that can be examined in this model.
Localised CAG expansion in specific regions of the brain and in specific cell populations can now be studied within the context of their neurophysiological status. My laboratory developed methods to profile expansions in both genomic DNA and mRNA populations, allowing us to identify neuronal populations where the presence of a transgeneic protein with increased number of glutamine residues might drive dysfunction. In particular, we have focussed on the cells in the cortico-striatal axis, where collaborative work with Dr Kerry Murphy's laboratory has identified very early dysfunction in dopaminergic cells that can be reveresed pharmacologically.
Molecular profiling of non-coding RNAs and the use of bioinformatic approaches to study normal and abnormal cell function are more recent areas of research interest with projects examining miRNA and gene expression in cancers.
Working with Prof Kay Davies (Oxford, 1988-1993) we used novel human DNA markers isolated from a chromosome microdissection library, in combination with YAC and physical mapping, to create the first long range map across the Xq27-28 region; mapping that was at the forefront of the developing technologies of human genome analysis in the late 1980’s and early 1990’s, integrating the use of chromosome microdissection, cell hybrid analysis, YAC screening, PFGE and FISH to first identify DNA markers flanking the Fragile X region and then to clone and identify the mutated region and detect abnormal methylation.
These studies led to the first identification of methylation mutations in fragile X individuals. I undertook an extensive screening of fragile X cohorts and published the first cases of molecular prenatal diagnosis for fragile X syndrome, published in Lancet in 1991. The Oxford FMR1 DNA probes are still used for carrier diagnosis world-wide. Unusual cases requiring detailed molecular investigation arose from collaborative screening programmes and from these I characterised six FMR1 deletions further contributing to our understanding of the disease mechanism. Population studies on a large fragile X cohort with genetic markers established a clear founder effect within European families for fragile X syndrome. We described the first accurate localisation of FRAXE and FRAXF and subsequently cloned the expanded triplets underlying these fragile sites. DNA probes for FRAXE and FRAXF are routinely used in diagnostics. I developed a PCR/sequencing technique which allowed me to analyse in detail the structure of over 100 normal human FMR1 arrays. Population profiling showed that precursor arrays with long stretches of uninterrupted repeats are associated with high risk founder haplotypes. Application of this sequencing technology has also been used in population studies, where we discovered an Asian specific FMR1 allele.
With this knowledge of FMR1 array structure, I developed a cloning system in which I have isolated a range of normal, precursor, premutation and expanded arrays, funded as a personal award from the Wellcome Trust (1993-1999). These form the basis for experiments studying array instability in several model systems including yeast and mouse. Transgenic studies in yeast are one focus of laboratory work and genetic screens have identified one pathway involving the key DNA replication components FEN1 and EXO1 as influencing CGG expansion. The homologous human genes have now been cloned and are being examined by deletion, over-expression and mutagenesis in both yeast and human cells, where we have developed two FEN1 directed ribozymes for gene ablation. Cloned arrays mimicking fragile X expansions are being used in several models systems to study instability and gene silencing, including work using Xenopus oocyte extracts that show the assembly of chromatin around the CGG arrays is influenced by the length of array and it’s methylation status. Work with CGG arrays has proven technically difficult, with analysis of repeat instability limited by the properties of the repeat itself, being refractory to the PCR studies that are really required to answer key questions of how expansion arises and how the cellular and physiological environment in defined groups of cells influences this process.
Understanding the relationship between somatic expansion of CAG repeat in the development and progression of Huntington’s disease
We are currently examining the profiles of CAG expansion within defined anatomical and neurophysiological populations of cells with different regions of the HD brain with the aim of relating somatic expansion to cellular dysfunction.
The role of DNA damage, repair and replication in triplet expansion
We are examining the effects of cell-cell differences in various DNA repair pathways upon the rate and extent of expansion of CGG and CAG triplet repeats within populations of cells within the brain an din several cellular model systems.
The effects of CGG expansion upon chromosome biology
We are examining the relationship between CGG repeat structure, replication and recombination.
Modules taught within the Open University's Natural Sciences and HealthSciences undergraduate programmes include:
Laboratory skills for Biology and Health (SS022; level 2) Laboratory school developing GMP and GLP applying molecular an dmicrobiologicalk approaches to studying antibiotic resistance.
Further laboratory skills for Biology and health (SS032; level 3) Laboratory school using advanced molecular to quantitate RNA and protein expression.
Practical Science (Biology and Health) (SXHL288; level 2, 30 points) Online and remote practical and investigational module.
Biological science: from genes to species. (S317; Level 3, 60 points). Author of topics on genomes and genome evolution (including genome database exploration and analysis) and on non-coding RNA functions. Academic lead for research skills strand within the module covering digital and information literacy, reading scientific literature and experimental investigations.
Biology of Survival. S295 (Level 2, 30 points) Author for research skills materials (Digital literacy, scientific reading and investigations).
Human Genetics and Health Issues (SK195; Level 1, 10 points)
Molecular Basis of Human Disease: How genetic variation affects susceptibility to HIV infection (SXR376 ; Level 3, 15 points)- Laboratory based module.
Molecular and Cell Biology (S377 ; Level 3 30 points) Author (DNA structure, repair and replication). Lead on scientific literature strand.
Projects that I have worked on include:
Open University/BBC Productions:
Advised on material and content of BBC/OU Cell City web site http://www.open2.net/science/cellcity/ Dramatic Science on ‘Cloning’ and appeared on Science Night investigation of Cloning and Dolly the Sheep. http://www.open2.net/dramaticscience/cloning/biology.htm., developed Bloodlines, & act as an ongoing advisor for the popular ‘Bang goes the Theory ( BBC1) programme.
I was the academic consultant and also made a personal appearance on BBC4 two part series The Gene Code (http://www.bbc.co.uk/programmes/b010j64w) that explores the progress in understanding of the human genome since it was first decoded. (BBC4, 2 x 60 minutes, broadcast April 2011). Project involved working with the Furnace production company to shape the academic content of the programmes. Example clip: https://www.youtube.com/watch?v=q71DWYJD-dI&list=PL70342B248B6C870D&index=5
As part of this project I developed an outreach and education kit of a human genome chromosome magnet set with a handy guide to genes on human chromosomes which were also linked to an article on BBC TV/Open University co-production Bang Goes the Theory (2011) that I worked as a scientific adviser for (http://www.bbc.co.uk/programmes/b00lwxj1).
A web site and genetic quiz called Unzip Your Genes was also produced to support the programmes, co-authored by Dr Rosa Hoekstra, which focused on how we can lean about human genetics using twin studies. http://www.open.ac.uk/openlearn/science-maths-technology/science/biology/unzip-your-genes
Open University/Newton Channel Productions:
I presented the DNA helix as one of the icons of the 20th Century. This is collaboration with the Science museum and the video is available through the Newton Channel http://www.guardian.co.uk/science/video/2010/nov/30/dna-double-helix-watson-crick
I worked on development of teaching materials for Living Links, which is is a field station and research centre of the University of St Andrews, established in partnership with the Royal Zoological Society of Scotland and Edinburgh Zoo. http://www.living-links.org/resources/. This involved creating a set of chromosomes (as hands-on assets and online teaching packs) showing the evolutionary relationship between human and chimpanzee chromosomes. http://www.living-links.org/resources/materials-for-teachers/chimpanzee-and-human-chromosomes-teacher-pack/
Open University publicity talks on the Human Genome project at the Natural History Museum, Birmingham ‘Thinktank’ and the Museum of Wales, Cardiff. I have given numerous talks to various community groups on Genetics and Cloning and Reproductive technologies.
Science into Schools and Colleges:
I am a member and registered speaker with Biology 4all, a web-based scheme to bring life sciences research into schools. (http://www.biology4all.com/). I have given numerous talks to schools on human genetics and health issues.
|Biomedical Research Network (BRN)||Network||Faculty of Science|
|Molecular Genetics Research Group||Group||Faculty of Science|
|Neuroscience Research Group||Group||Faculty of Science|
|Role||Start date||End date||Funding source|
|Co-investigator||01 Oct 2015||30 Sep 2018||Sheffield Teaching Hospitals|
Intercellular communication between immune cells and tissue-resident cells is essential to coordinate an effective immune response and involves both cell-contact dependent and independent processes that ensure the transfer of information between bystander and distant cells. There is a rapidly growing body of evidence on the pivotal role of extracellular vesicles (EVs) in cell communication and these structures are emerging as important mediators for immune modulation upon delivery of their molecular cargo. In the last decade, EVs have been shown to be efficient carriers of genetic information, including microRNAs, that can be transferred between cells and regulate gene expression and function on the recipient cell. However, little is known about regulation of cellular function by EVs at the blood-brain barrier (BBB), the main route of entry of immune cells into the central nervous system (CNS), in pathological conditions. We have recently shown that EVs isolated from MS patients induce blood-brain barrier dysfunction, characterised by leakiness of the barrier, in a human culture model (1) and that the microRNA profile of brain endothelium undergoes profound changes in inflammation (2,3). Thus, the proposed project will investigate the role of microRNAs secreted in EVs in activation of brain endothelium and subsequent leukocyte migration. In year 1, the miroRNA profile of EVs released by cultured human brain endothelium in inflammatory conditions and in plasma of MS patients will be determined. In year 2, the effects of endothelial-derived and MS plasma-derived EVs on leukocyte adhesion, both leukocyte cell lines and peripheral blood mononuclear cells, under flow will be investigated. In year 3, specific microRNAs will be knocked-down in cultured human brain endothelium prior to EV collection and subsequent effects on leukocyte adhesion will be investigated
Are there any HOTTIPs for defining coding potential of lncRNAs, or just a lot of HOTAIR? (2017-07-27)
Mather, Rebecca L.; Hirst, Mark and Crea, Francesco
Epigenomics, 9(8) (pp. 1045-1047)
Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington’s Disease (2016-03-01)
Dallerac, Glenn M.; Cummings, Damian M.; Hirst, Mark C.; Milnerwood, Austen J. and Murphy, Kerry P. S. J.
NeuroMolecular Medicine, 18(1) (pp. 146-153)
Dysfunctional Dopaminergic Neurones in Mouse Models of Huntington's Disease: A Role for SK3 Channels (2015-04-09)
Dallerac, G.M.; Levasseur, G.; Vatsavayai, S.C.; Milnerwood, A.J.; Cummings, D.M.; Kraev, I.; Huetz, C.; Evans, K.A.; Walters, S.W.; Rezaie, P.; Cho, Y.; Hirst, M.C. and Murphy, K.P.S.J.
Neurodegenerative Diseases, 15(2) (pp. 93-108)
Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation. (2015-03-01)
Wu, Dongsheng; Cerutti, Camilla; Lopez-Ramirez, Alejandro; Pryce, Gareth; King-Robson, Josh; Simpson, Julie E.; van der Pol, Susanne M. A.; Hirst, Mark C.; de Vries, Helga E.; Sharrack, Basil; Baker, David; Male, David K.; Michael, Gregory J. and Romero, Ignacio A
Journal of Cerebral Blood Flow & Metabolism, 35(3) (pp. 412-23)
MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation. (2014-06-01)
Lopez-Ramirez, Miguel Alejandro; Wu, Dongsheng; Pryce, Gareth; Simpson, Julie E.; Reijerkerk, Arie; King-Robson, Josh; Kay, Oliver; de Vries, Helga E.; Hirst, Mark C.; Sharrack, Basil; Baker, David; Male, David Kingsley; Michael, Gregory J. and Romero, Ignacio Andres
FASEB Journal, 28(6) (pp. 2551-2565)
Impaired long-term potentiation in the prefrontal cortex of Huntington’s disease mouse models: rescue by D1 dopamine receptor activation (2011-05)
Dallérac, G. M.; Vatsavayai, S. V.; Cummings, D. M.; Milnerwood, A. J.; Peddie, C. J.; Evans, K. A.; Walters, S. W.; Rezaie, P.; Hirst, M. C. and Murphy, K. P. S. J.
Neurodegenerative Diseases, 8(4) (pp. 230-239)
Abnormal cortical synaptic plasticity in mice transgenic for exon 1 of the human Huntington's protein (2007-04-30)
Cummings, Damian M.; Milnerwood, Austen J.; Dallerac, Glenn M.; Vatsavayai, Sarat C.; Hirst, Mark C. and Murphy, Kerry P. S. J.
Brain Research Bulletin, 72(2-3) (pp. 103-107)
Progressive CAG expansion in the brain of a novel R6/1-89Q mouse model of Huntington's disease with delayed phenotypic onset (2007-04-30)
Vatsavayai, Sarat C.; Dallerac, Glenn M.; Milnerwood, Austen J.; Cummings, Damian M.; Rezaie, Payam; Murphy, Kerry P.S.J. and Hirst, Mark C.
Brain Research Bulletin, 72(2-3) (pp. 98-102)
Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of huntington's disease (2006-10-01)
Cummings, Damian M.; Milnerwood, Austen J.; Dallerac, Glenn M.; Waights, Verina; Brown, Jacki Y.; Vatsavayai, Sarat C.; Hirst, Mark C. and Murphy, Kerry P. S. J.
Human Molecular Genetics, 15(19) (pp. 2856-2868)
Early development of aberrant synaptic plasticity in a mouse model of Huntington's disease (2006-05-15)
Milnerwood, Austen J.; Cummings, Damian M.; Dallerac, Glenn M.; Brown, Jacki Y.; Vatsavayai, Sarat C.; Hirst, Mark C.; Rezaie, Payam and Murphy, Kerry P.S.J.
Human Molecular Genetics, 15(10) (pp. 1690-1703)
Fragile X (CGG)n repeats induce a transcriptional repression in cis upon a linked promoter: evidence for a chromatin mediated effect (2003-03)
Chandler, Simon P.; Kansagra, Pushpa and Hirst, Mark C.
BMC Molecular Biology, 4(3)
Instability of a (CGG)(98) repeat in the Fmr1 promoter (2001-08-01)
Bontekoe, C.J.M.; Bakker, C.E.; Nieuwenhuizen, I.M.; van der Linde, H.; Lans, H.; de Lange, D; Hirst, M.C. and Oostra, B.A.
Human Molecular Genetics, 10(16) (pp. 1693-1699)
Practical biology at a distance: how far can we go with online distance learning? (2016-07-31)
Hirst, Mark C. and MacQueen, Hilary A.
In: Kennepohl, Dietmar ed. Teaching Science Online: Practical Guidance for Effective Instruction and Lab Work. Online Learning and Distance Education
ISBN : 978-1620361870 | Publisher : Stylus Publishing | Published : Sterling, VA, USA
The Fragile X Syndrome and the Fragile X Mutation (2003-01)
Hirst, Mark C. and Fisch, Gene S.
In: Fisch, Gene S. ed. Genetics and Genomics of Neurobehavioral Disorders. Contemporary Clinical Nueroscience (pp. 335-390)
ISBN : 1-59259-353-4 | Publisher : Humana Press | Published : USA
Identification of candidate genes that may function in ER- breast cancer (2018)
Chandler, Stephen; Crea, Francesco; Hirst, Mark; Cox, Angela and Rigas, Sushila
In : BACR Conference: Response and Resistance in Cancer Therapy (10-12 Sep 2018, University of Kent, Canterbury)
Identification of putative functional genes in breast and other cancers with potentially shared aetiology (2017-11-23)
Chandler, Stephen; Crea, Francesco; Hirst, Mark; Cox, Angela and Rigas, Sushilaben
In : The Human Genome in Healthcare (23-24 Nov 2017, The Royal Society, London, UK)