Research output per year
Research output per year
Haematopoiesis is largely conserved throughout evolution and has been a long term a paradigm to study stem cell, lineage specification and gene regulation. So far, it has elucidated many major principles of how mammalian genes are regulated during development and differentiation, but also how dysfunction of such regulation can lead to human disease.
Research on haematopoiesis at the University of Edinburgh has expanded dramatically over the last few years. Recently, eleven laboratories gather together to launch “The Edinburgh Haematopoiesis Network” (EHN).
The EHN programme covers many aspects of normal and malignant haematopoiesis from cell biology and mouse/zebrafish models to genetics and epigenetics. The EHN is thus a multidisciplinary network addressing important haematopoietic questions. More specifically, we are studying the origin of haemotopoietic stem cells, the bone marrow niche, the production of blood cells, and the genes involved in cell specification, which includes lineage specific transcription factors, and epigenetics regulation. How abnormal expression of these genes can lead to cancer and leukaemia is also covered.
Network Members:
Douglas Vernimmen: Epigenetic Regulation during Normal and Leukaemic Haematopoiesis |
Douglas Vernimmen read Biology (BSc) and Molecular Biology (MSc) and gained his PhD in Biochemistry at the University of Liège (Belgium) in 2003. His work was under the supervision of Dr Rosita Winkler (Department of Pathology, Prof Boniver), and was focused on the characterisation of an enhancer element involved in the overexpression of an oncogene in breast cancers. Afterwards, he moved to the University of Oxford (England) in the Weatherall Institute of Molecular Medicine as a MRC Postdoctoral fellow, under the supervision of Prof Doug Higgs (Molecular Haematology Unit). Using a-globin regulation as a model, he showed the role of enhancer elements in the recruitment of transcription factors, but also chromosomal looping and epigenetic changes required for gene transcription. During these years, he has developed an international reputation in the gene transcription field, and more particularly in chromosome looping studies where he developed a quantitative method to measure interaction between different DNA elements (q3C, Chromosome Conformation Capture). Overall, his work has always been dedicated on the understanding of how mammalian genes are switched on and off during differentiation to control cell fate and to specify different lineages, but also how genes are abnormally regulated in genetic diseases such as cancer and thalassaemia. Douglas is now an independent scientist at The University of Edinburgh (Scotland), running his group at The Roslin Institute. His work is now focussed on transcription activity in individual cells and epigenetic regulation in leukaemia.
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Andrew Wood is a Chancellor’s Fellow, Sir Henry Dale Fellow and group leader at the Institute for Genetics and Molecular Medicine. His laboratory studies the cell cycle regulation of chromosome structure, and is using murine haematopoiesis as a model system to study links between cell cycle regulation and chromosomal instability in primary differentiating cells. During his PhD at King’s College London, Andrew identified several novel imprinted genes and showed for the first time that CpG methylation could regulate the production of variant transcripts through alternative polyadenylation. His post-doctoral work was conducted at the University of California, Berkeley, where he pioneered the use of genome editing technologies to modify DNA sequences in the animal germline. His group maintains an active research interest in genome editing technologies based on the TALEN and CRISPR/Cas9 platforms
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Maria Christophorou |
Biography Maria studied Biology at MIT, where she was funded by a Fullbright scholarship. During that time she studied the development of the zebrafish nervous system in the laboratory of Prof. Hazel Sive, at the Whitehead Institute. Her doctoral work was completed in the laboratory of Prof. Gerard Evan, at the UCSF Comprehensive Cancer Center, where she studied the relative contributions of different p53 activating signals towards tumour suppression. In order to expand her expertise into basic biochemistry and molecular biology, she joined the laboratory of Prof. Tony Kouzarides at the Gurdon Institute, University of Cambridge, with support from Long-Term post-doctoral fellowships from EMBO and HFSP. There, she uncovered a new role for the peptidylarginine deiminase PADI4 in the regulation of pluripotency and described a molecular mechanism by which it mediates chromatin decondensation. In 2014 she was awarded a Chancellor’s fellowship from the University of Edinburgh and a Sir Henry Dale fellowship form the Wellcome Trust and Royal Society to establish an independent research group at the MRC Institute of Genetics and Molecular Medicine. She holds a 2014 Wellcome Beit Prize. Research Summary The number of protein-coding genes in the genome does not nearly account for the number of processes necessary for an organism’s vital functions. Small chemical changes, called post-translational modifications (PTMs), are made on proteins by enzymes and determine when, where and how proteins work. As such, PTMs fine-tune protein function and add an enormous degree of sophistication to biological systems. By the same token, abnormal deposition of PTMs by malfunctioning modifying enzymes can deregulate proteins and upset normal cellular function in the same way that a mutation in a critical gene would. Importantly, the modifying enzymes lend themselves to modulation by externally added compounds (such as specific chemical inhibitors) and therefore understanding the way they work presents exciting possibilities for therapeutic intervention. The PTM citrullination (or deimination) is the conversion of an arginine residue to the non-coded amino acid citrulline. It is carried out by enzymes called peptidylarginine deiminases (PADIs) and can modulate a protein's function by altering its structure, changing its sub-cellular localisation and affecting its interactions with other molecules. Our recent work has shown that citrullination regulates pluripotency, the ability to generate any type of cell from a stem cell, which holds great promise for regenerative medicine. Notably, abnormal citrullination is a pathological feature of diseases such as autoimmunity (rheumatoid arthritis, multiple sclerosis, ulcerative colitis, psoriasis), neurodegeneration (Alzheimer's and prion diseases) and cancer. In certain cases it serves as a diagnostic and prognostic marker, while its inhibition has shown early promise in disease-based experimental systems. Despite the likely mechanistic importance of citrullination in both cell physiology and disease, it remains largely unexplored. The central aims of our work are to understand how PADIs are regulated, how they modulate normal cell function and how their deregulation contributes to disease development. We employ a combination of biochemical, molecular and cell biological approaches, as well as in vivo model systems. We hope that this work will significantly advance our current understanding of citrullination and explore new regulatory mechanisms involved in both physiology and disease.
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Research Interests Our research is focused on identifying and characterizing the molecular processes involved in the differentiation of haematopoietic cells in culture from pluripotent cells such as embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs). Pluripotent cells are able to differentiate in vitro into many cell types and this system has been used as a model to study developmental and diseases processes as well as providing a source of cells for regenerative medicine. However, it has proven difficult to produce pure populations of mature cell type in high numbers. Our research is focused on optimizing the differentiation protocols for the production of haemotopoietic (blood) cells from pluripotent stem cells in vitro using knowledge obtained from the study of these cell types during development in vivo. We are involved in an exciting collaborative project with colleagues in the Scottish National Blood Transfusion Service, NHS-BT and the Universities of Glasgow, Bristol, Cambridge and Loughborough to produce red blood cells in the laboratory with the ultimate aim of using these cells as an alternative to blood transfusion. We have generated a number of iPSC lines of specific blood groups and we are using transcription factors to enhance the production and maturation process. We generated a number of reporter cell lines to track the expression of key transcription factors and are using these to optimise and refine the differentiation process. We can also differentiate pluripotent cells into large numbers of other mature blood cell types including macrophages that are the key cell type involved in inflammation. We are currently using our in vitro-generated macrophages as a therapeutic tool in models of inflammatory diseases. In collaboration with Professor Stuart Forbes we are testing these cells as therapy in mouse model of liver fibrosis.
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Biography I studied biology at Beijing Normal University, and obtained BSc degree in 1997. I did my postgraduate research at the Beijing Institute of Biotechnology, Academy of Military Medical Sciences, China, and obtained my PhD in Genetics in 2002. I came to the UK in November 2004 and joined Dr Qiling Xu’s lab at the National Institute for Medical Research, where I gained experience in zebrafish development and genetics and investigated the function of transcription factors Hmx2&3 during zebrafish sensory organ lateral line development. I soon became aware of the unique opportunities afforded by zebrafish to model human disease; not only being amenable to genetic manipulation, but importantly, translucency of larvae allows for live imaging, in real time following genetic or pharmacological interference. This leads to a radical change in my research focus. I joined Professor Paul Martin’s lab at the University of Bristol in March 2007, where I lead the zebrafish research projects on the function of innate immunity during wound healing and tumour initiation. I have successfully established a zebrafish model for live imaging studies of the earliest events of tumourigenesis in vivo, and my research has lead to the discovery of a host trophic inflammation response toward newly emerged oncogene transformed-cells within host tissue. I was then funded by an ISSF Wellcome Trust grant from the university of Bristol for 6 months to consolidate my research before I awarded a Chancellor’s Fellowship to join the MRC Centre for Inflammation Research at the University of Edinburgh in October 2012. Here in Edinburgh, I continue my research on live imaging of the earliest events of tumourigenesis in a zebrafish model and I received Wellcome Trust Sir Henry Dale Fellowship and Wellcome Trust-Beit Prize in 2013. My research now is focusing on the regulation of Trophic inflammation response during tumour initiation. We have set up an inducible tumourigenesis system in zebrafish skin for our live imaging studies. We are also embarking on a new project to establish the first zebrafish B cell lymphoma model. |
Person: Academic: Research Active
Person: Academic: Research Active
Person: Academic: Research Active
Research output: Contribution to journal › Article › peer-review
Research output: Contribution to journal › Article › peer-review
Research output: Contribution to journal › Review article › peer-review
Douglas Vernimmen (Organiser), Sari Pennings (Organiser), Kamila Malysz (Speaker), James Watson (Speaker) & Elias Friman (Speaker)
Activity: Participating in or organising an event types › Participation in workshop, seminar, course
Douglas Vernimmen (Trainer)
Activity: Participating in or organising an event types › Public Engagement – Schools engagement
Douglas Vernimmen (Organiser) & Sari Pennings (Organiser)
Activity: Participating in or organising an event types › Participation in workshop, seminar, course
Vernimmen, Douglas (Recipient) & Mortimer, Tom (Recipient), 2 Nov 2019
Prize: Prize (including medals and awards)
Blackburn, Clare (Recipient), 2014
Prize: Prize (including medals and awards)
Blackburn, Clare (Recipient) & Hardie, Amy (Recipient), 2012
Prize: Prize (including medals and awards)
1/01/18 → 31/07/18
Project: University Awarded Project Funding
Glykofrydis, F. (Owner), Popravko, A. (Creator), Dzierzak, E. (Owner), Davies, J. (Owner), Romanowski, A. (Data Manager) & Zielinski, T. (Data Manager), Edinburgh DataVault, 30 Jan 2021
DOI: 10.7488/387d2274-5678-4626-a138-732ba80a767c
Dataset
Liu, D. (Creator), Kousa, A. I. (Creator), Tomlinson, S. R. (Creator) & Blackburn, C. (Creator), National Center for Biotechnology Information (Gene Expression Omnibus), 10 Jun 2020
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE100314
Dataset
17/06/24
2 Media contributions
Press/Media: Research
Douglas Vernimmen & Georgia Goddard
29/09/23
1 Media contribution
Press/Media: Research