We are interested in understanding how epigenetic marks are placed, read and interpreted on chromatin. Chromatin becomes decorated with post-translational modifications to control the myriad of DNA-related processes in the cell. We create 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 to investigate histone marks and DNA methylation.
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 themethylation 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 signaled on chromatin and how this leads to correct repair.
Nucleosome modifications act as a central signaling hub in this network to organise responses to a neighbouring break. While many factors are known to localise to modified DSB-adjacent chromatin, the exact function and binding of many of these proteins is unclear. We plan to focus on biochemically and structurally characterising nucleosome ubiquitylation proteins involved in DNA damage repair.
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- Wilson, M.D.¶, and Durocher, D. (2017). Reading chromatin signatures after DNA double-strand breaks. Philos Trans R Soc Lond B Biol Sci 372. PubMed
- Kitevski-LeBlanc, J., Fradet-Turcotte, A., Kukic, P., Wilson, M.D., Portella, G., Yuwen, T., Panier, S., Duan, S., Canny, M.D., van Ingen, H., et al. (2017). The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage. Elife 6. PubMed
- Wilson, M.D.¶, and Costa, A.¶ (2017). Cryo-electron microscopy of chromatin biology. Acta Crystallogr D Struct Biol 73, 541-548. PubMed
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* co-first authors ¶ corresponding author(s)