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.
- Becker JR, Clifford G, Bonnet C, Groth A, Wilson MD, Chapman JR. (2021) BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination. Nature. 2021 Jul 28. doi: 10.1038/s41586-021-03776-w. Pubmed
- Belotserkovskaya, R. ¶, Raga Gil, E., Lawrence, N., Butler, R., Clifford, G., Wilson, M. D. ¶, & Jackson, S. P¶. (2020). PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1. Nature communications, 11(1), 819. Pubmed
- Murawska, M., Schauer, T., Matsuda, A., Wilson, M. D., Pysik, T., Wojcik, F., … Ladurner, A. G. (2020). The Chaperone FACT and Histone H2B Ubiquitination Maintain S. pombe Genome Architecture through Genic and Subtelomeric Functions. Molecular cell, 77(3), 501–513. Pubmed
- Salguero I, Coates J, Belotserkovskaya R, Sczaniecka-Clift M, Demir M, Jhujh S, Wilson MD, Jackson SP. MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance. (2019) Nature Communications 10(1):5191 Pubmed
- Wilson MD*, Renault L*, Maskell D, Ghoneim M, Pye VE, Nans N, Rueda DS, Cherepanov P, Costa A. Retroviral integration into nucleosomes through DNA looping and sliding along the histone octamer (2019) Nature Communications 10(1):4189. Pubmed
- Vidakovic AT, Harreman M, Dirac-Svejstrup AB, Boeing S, Roy A, Encheva V, Neumann M, Wilson MD, Snijders AP, Svejstrup JQ. Analysis of RNA polymerase II ubiquitylation and proteasomal degradation. (2019) Methods pii: S1046-2023(18)30312-8. doi: 10.1016/j.ymeth.2019.02.005. Pubmed
- Canny, M.D., Moatti, N., Wan, L.C.K., Fradet-Turcotte, A., Krasner, D., Mateos-Gomez, P.A., Zimmermann, M., Orthwein, A., Juang, Y.C., Zhang, W., et al. (2018). Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nat Biotechnol 36, 95-102. PubMed
- 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
- Wilson, M.D.*, Benlekbir, S.*, Fradet-Turcotte, A., Sherker, A., Julien, J.P., McEwan, A., Noordermeer, S.M., Sicheri, F., Rubinstein, J.L., and Durocher, D. (2016). The structural basis of modified nucleosome recognition by 53BP1. Nature 536, 100-103. PubMed
- Orthwein, A.*, Noordermeer, S.M.*, Wilson, M.D., Landry, S., Enchev, R.I., Sherker, A., Munro, M., Pinder, J., Salsman, J., Dellaire, G., et al. (2015). A mechanism for the suppression of homologous recombination in G1 cells. Nature 528, 422-426. PubMed
- Wilson, M.D.*, Harreman, M.*, Taschner, M., Reid, J., Walker, J., Erdjument-Bromage, H., Tempst, P., and Svejstrup, J.Q. (2013). Proteasome-mediated processing of Def1, a critical step in the cellular response to transcription stress. Cell 154, 983-995. PubMed
- Wilson, M.D., Harreman, M., and Svejstrup, J.Q. (2013). Ubiquitylation and degradation of elongating RNA polymerase II: the last resort. Biochim Biophys Acta 1829, 151-157. PubMed
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- Patton, D.T., Wilson, M.D., Rowan, W.C., Soond, D.R., and Okkenhaug, K. (2011). The PI3K p110delta regulates expression of CD38 on regulatory T cells. PLoS One 6, e17359. PubMed
* co-first authors ¶ corresponding author(s)