Background

1. The Chromatin Lab, the Developmental Biology Division and The Roslin Institute.

The new Roslin Institute (launched in 2011) has developed a broad panel of interests, and has a wide portfolio spanning genetics and developmental biology. The Developmental Biology Division aims to enhance fundamental knowledge of the control of cellular growth and differentiation, to underpin the development of better disease intervention strategies. We advance our understanding of function in these essential biological processes through mechanistic studies at the cell, tissue and whole organism level with particular focus on stem cells, tissue and organ development, tissue damage and repair and regulatory networks in development. The regulation of gene expression is at the basis all these biological processes and the mission of the Chromatin Lab is to bring new angles to the institute with our expertise in chromatin and epigenetics.

The overall aim of the Chromatin Laboratory is to understand 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. More specifically, we aim to understand the role of enhancers in this process, using haematopoiesis as a model system.

2. Epigenetics and Transcription Regulation.

Epigenetics is the study of the changes in gene expression due to modifications to the genome that do not involve a change in the nucleotide sequence. It is now clear that one form of epigenetic regulation involves the establishment/removal of histone post-translational modifications. These changes are catalysed by a panel of different enzymes (called chromatin-modifying enzymes or epigenetic regulators), which target specific genes for activation or inactivation. The last decade has led to the identification of many of these enzymes, which are required for transcription regulation, cell cycle and differentiation. Today, the field is just beginning to understand the regulation of these enzymes and the biological significance of histone modifications. These enzymes have also generated a clinical interest since drugs can be designed to modulate their activity, which has launched the development of epigenetic therapy.

Remote regulatory sequences (enhancers) have been defined as DNA elements responsible for increasing the transcription level of a target gene, located sometimes very far away. What do these sequences really do and how do they work at very large distances? These have been questions of major interest over the last two decades. Today it is well accepted that remote enhancers function as docking sites for the recruitment of the general transcription machinery, which would be subsequently transferred to a target promoter by a looping mechanism.

Over the last decade, the Encyclopedia of DNA Elements (ENCODE) project aimed to map all functional elements (e.g. enhancers, promoters, coding regions, methylated DNA sequences) in the human genome. The recent “completion” of the ENCODE project (2012) has revealed that there are many more enhancers than expected. Also, genome-wide associated studies (GWAS) showed that many single nucleotide polymorphisms (SNPs), associated with susceptibility/resistance to a disease, have been found outside gene coding sequences emphasizing the importance of enhancers.

Research Programme

Our current research programme is focused on two main aspects of enhancers:

1. Enhancer Activity.

Summary: There is a body of evidence that variation of expression at a single cell basis occurs (subpopulations). This highlights the need for techniques to approach chromatin architecture in single cells, as this would directly capture cell-to-cell variation. We use genetic engineering techniques in order to make models in which we can visualise transcription activity in individual cells.

Funding: Early Stage Investigator Start-up Fellowship, British Society for Haematology (BSH).

2. Enhancer Functions.

Summary: During development and cell differentiation, epigenetic regulators are required to dramatically alter epigenetic programmes and therefore gene expression states to create new cell-specific profiles. Our aim is to understand how transcription enhancers control the epigenetic programme using an approach integrating molecular biology, bioinformatics and genetics. We will also test existing compounds and produce new inhibitors for epigenetic regulators in leukaemia. These have strong potential for the development of epigenetic therapy in the future.

Funding: Kay Kendall Leukaemia Fund.

PhD Students:

- Kamila Malysz (2020-2023)
 Project: "Role of Demethylases in Myeloid leukaemia"

-Ailbhe Brazel (2013-2016)
 Project: "Long Range Control of Epigenetic Regulation"

Honours Students:

-Miren Urrutia Iturritza (2017)

-Eirini Kallimasioti Pazi (2015)

Summer Students:

- Elise Georges (2018)
 Project: "Chromosomal Alterations in Acute Myeloid Leukaemia"

-Justin Auerbach (2015)
 Project: "CRISPR/Cas9 mediated enhancer deletion in mouse ES cells"

-Ami Patrick (2014)
 Project: "Analysis of epigenetic regulators expression in normal haematopoietic  and leukaemic cells"

-Sarah Mounedji (2014)
 Project: "Generation of knock-in cells with a fluorescent reporter gene"

http://www.youtube.com/watch?v=yLdpMcpwyFw

Welcome to the Chromatin Laboratory, run by Dr Douglas Vernimmen and part of the Developmental Biology Division at The Roslin Institute. Dr Vernimmen introduces his laboratory and gives insight into his team's work, before each of his team members gives a brief overview of their position and role.

Prof Juri Rappsilber, University of Edinburgh

Dr Peter Hohenstein, University of Edinburgh

Dr Andrew Smith, University of Edinburgh

Prof Doug Higgs, University of Oxford

Prof Willem Ouwehand, University of Cambridge

Dr Yufeng Tong, University of Toronto

Prof Peter Andrews, University of Sheffield

Prof David Hume, University of Edinburgh

Prof Kamil Kranc, University of Edinburgh

Prof Chris Ponting, University of Edinburgh

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 alpha globin regulation as a model, he showed the role of enhancer elements into the recruitment of transcription factors but also chromosomal looping and the epigenetic changes required for gene transcription.

During these years, Doug 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 to 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.

Beside his scientific work, Douglas is also the recipient of over 200 awards and distinctions for his international contribution to Photography, and recently published a book, “Oxford Through the Lens”, aiming to fund scholarships at the University of Oxford.

Genetics Society: Local Representative for the Roslin Institute

Genetics Society: Ordinary Committee Member (Representative for Area A - Gene Structure, Function and Regulation)

Associate Member of Brasenose College, University of Oxford.

Member of the Belgian Society of Biochemistry and Molecular Biology

Member of the Belgian Association for Cancer Research (BACR)

Member of the Genetics Society

Member of the British Society for Haematology

Member of the International Society for Experimental Hematology

Member of the British Society for Cell Biology

Elected Member Genetics Society Ordinary Committee Member (Representative for Area A - Gene Structure, Function and Regulation)

Member of the Oxford Photographic Society (2004-2012)

Member of the Royal Photographic Society 

Member of Image sans Frontiere 

Member of the Photographic Society of America 

Member of the Edinburgh Photographic Society

Photographic Distinctions (EPSA, EFIAP, EH-ISF, RISF3, LRPS, CPAGB, BPE1*) and International Photography Awards (FIAP, PSA, RPS, IPA, PX3, AOP & PDN).

Website at http://www.douglasvernimmen.com/

Postdocs:

- Dr William Ho (2029-2020)

- Dr Darya Deen (2018-2020)

- Dr Louie van de Lagemaat (2016-2017)

- Dr Ali Anvari Azar (2017-2020)

Our collaborative research with Prof K Kranc is to address the precise functions of epigenetic regulators in myeloid leukaemia using in vitro, ex-vivo and in vivo models. Together with additional screening in patients for mutations in this gene, this research will enable us to develop new approaches to treat leukaemia.

http://www.ed.ac.uk/roslin/chromatin-biology-epigenetics