Nick Gilbert Lab: www.chromatinlab.org

During my PhD in the lab of Dr Jim Allan (Edinburgh University) I trained in classical biochemistry and biophysical approaches to investigate chromatin, giving me a deep understanding of the fundamental structural organisation of chromatin fibres. Subsequently I undetook postdoctoral training with Professor Wendy Bickmore (MRC Human Genetics Unit) where I used approaches to study higher order chromatin structure and nuclear organisation in mammalian cells and developed a new technique to generate the first genome wide chromatin structure map. I started my own lab at the Edinburgh Cancer Research Centre with a fellowship from the Wellcome Trust in 2006 where we used new approaches to map the chromatin fibre structure of the active and inactive X chromosomes and relate this to large scale levels of chromatin organization. This work led me to develop a new molecule for mapping DNA structure. To achieve this I worked in the chemistry department for six months and learnt the basics in organic chemistry synthesis giving me a good understanding for the development of future tools for investigating chromatin structure. My lab moved to the MRC Human Genetics Unit in 2012 where I have an MRC Senior fellowship. My lab is now focused on investigating DNA topology across the human genome and how it can affect chromosomal instability and fragile site formation.

For a video of our work see http://www.nutshell-videos.ed.ac.uk/nick-gilbert-packaging-the-genome/

In mammalian cells DNA is wrapped around proteins to form chromatin. This protects DNA from damage and regulates gene transcription. Our lab is studying the protein and epigenetic factors that modify DNA and chromatin structure influencing gene expression and genome stability.

A key goal of our research is to understand how changes in chromatin structure affect gene expression and genome stability in disease. These studies will help us to understand this process and develop future drugs to treat diseases like cancer.

http://www.nutshell-videos.ed.ac.uk/nick-gilbert-packaging-the-genome/

Understanding the regulation and topological organisation of chromatin and DNA in the human genome.

Chromatin is folded at different levels of organisation from the fundamental nucleosomal fibre to higher order and large scale chromatin structures. Although chromatin has been studied for the last 40 years and the basic components of chromatin are known in considerable detail, the cellular structure of the chromatin fibre and fibre-fibre interactions are poorly understood. As the folding of the higher order chromatin and its modulation is critical to understanding many nuclear processes, there is a significant need for research in this area.

Our work is at the interface between molecular biology, nuclear biology and structural biochemistry. We develop new approaches to investigate the fundamental structure of the higher order chromatin fibre, large scale chromatin-chromatin interactions at high resolution and understand the impact of chromatin packaging on the regulation of DNA transcription, replication and repair and the subsequent consequences for human disease. We have strong interactions with the chemistry department (Mark Bradley) for making novel chromatin structure probes and engineering and physics to develop new instruments to analyse chromatin fibre structure and physics.

Key projects

1. DNA in cells is twisted by enzymes introducing supercoils, a process that is critical for the regulation of transcription, replication and repair. We are investigating the link between gene transcription, DNA supercoiling and large scale chromatin structure to understand this process and how the transcription of one gene can effect the transcription of surrounding genes.
2. Common fragile sites are regions in the genome that have a propensity to break under stress. The mechanism of common fragile site formation is unknown but it has been proposed that due to the chromatin/DNA environment these regions are very sensitive. We are studying changes in DNA supercoiling at CFSs to characterise the mechanisms responsible for genomic instability and provide a paradigm for the formation of other genomic abnormalities such as genomic rearrangements or gene fusions, that are often found in cancer.
3. A significant unresolved question in chromatin biology is the structure of the higher order chromatin fibre, predominantly due to a lack of experimental approaches to investigate it. We are developing high resolution cross-linkers to join pieces of DNA that are located in close proximity to each other in the chromatin fibre and map these interactions to build a chromatin fibre structure map for the human genome.