Marcus Wilson

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Marcus Wilson is a Sir Henry Dale Fellow in the Wellcome Centre for Cell Biology. His research focuses on understanding how epigenetic marks are deposited, read and removed on chromatin. His group primarily use structural biology approaches such as single particle cryo-electron microscopy (cryo-EM) and supplement this with biochemical and biophysical methods.

After Masters studies at the University of Oxford, UK, Marcus moved to the Cancer Research UK, Clare Hall laboratories in London to study for his PhD with Dr. Jesper Svejstup. Marcus then moved to a postdoctoral position with Prof. Daniel Durocher in the Lunenfeld-Tanenbaum research Institute in Toronto, Canada where he began working on cryo-EM; collaborating with Dr. John Rubinstein at the SickKids Research Institute in Toronto. Marcus then gained further cryo-EM experience during a two year postdoctoral position with Alessandro Costa at the Macromolecular Machines Laboratory at the Francis Crick Institute.

Marcus joined the University of Edinburgh and the Wellcome Centre for Cell Biology in July 2018.

Wilson lab website

Investigating the reading writing and erasing of epigenetic marks

We are interested in understanding how epigenetic marks are placed, read and interpreted on chromatin. Chromatin becomes decorated with a variety of chemical tags or epigenetic marks to control the myriad of DNA-related processes in the cell. Epigenetic modifications are initially deposited by writer enzymes. These are then read and interpreted in a co-operative manner by effector proteins. Epigenetic marks can also be removed by eraser proteins resetting the system (Figure 1 A). We look at this process in the test tube by creating modified chromatin using chemical biology and biochemical methods. We then use our defined modified chromatin to study individual nucleosome-chromatin protein complexes using single-particle cryo-electron microscopy (cryo-EM), Biochemical, Biophysical and Cell Biology approaches. We are particularly interested in understanding how DNA damage repair and DNA methylation pathways are orchestrated by epigenetically-modified nucleosomes.

How is DNA Methylation guided by chromatin?

DNA methylation is a common epigenetic mark that is often associated with turning off genes and compacting DNA. Other epigenetic marks have the power to regulate DNA methylation, controlling when and where DNA methylation is placed on DNA, but we do not understand how this works. We are rebuilding the DNA methylation machinery within chromatin to help us answer this question.

DNA methylation is a highly regulated process, so by looking at the structure of the methylation machinery and the modified nucleosomes we hope to understand how methylation is targeted at specific times and to specific sites on DNA, hopefully helping us to understand how this process can become faulty leading to disease.

How do post-translational modifications foster DNA repair?

DNA is under constant attack, which can cause unwanted genetic mutations and cancer. Luckily our cells have a host of DNA repair proteins, which help to fix most of the damage. These highly efficient repair proteins are recruited to sites of damage by recognition of DNA damage-specific marks on chromatin. We are hoping to understand how DNA damage is signalled on chromatin and how this leads to correct repair.

Our recent work has shown that multiple DNA repair proteins interact multivalently with the nucleosome, commonly interacting with a conserved region called the acidic patch (Figure 1B). Through our in vitro studies we showed that the negatively charged surface of the nucleosome acidic patch is essential for binding of the listed DNA damage proteins. Mapping of the interaction regions and mutation has shown these are mediated by electrostatic interactions, typically through a highly conserved arginine anchor.

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A. Schematic of the cycle of epigenetic modifications in the cell. All modifications focus on the nucleosome hub, which can be modified on both the histone proteins and wrapped DNA. Example Reader, writer and eraser proteins DNA damage repair and DNA methylation pathways are labelled.

B. Multivalent interactions in the DNA damage response focus on the acidic patch of the nucleosome.