Summary of Research

The Chromatin group's research interests.

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.

Current Project: "Long-Range Control of Epigenetic Regulation" (Ailbhe Brazel, PhD Student).  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.

Current Project: "Deciphering new roles of remote enhancer elements" (Iveta Gazova, PhD Student). Funding: Lady Tata Memorial Trust.

Collaborators

• Prof Kamil Kranc, University of Edinburgh
• Prof Juri Rappsilber, University of Edinburgh
• Dr Peter Hohenstein, University of Edinburgh
• Dr Andrew Smith, University of Edinburgh
• Prof Chris Ponting, 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