How do chromatin remodelling proteins and the nuclear gel collaborate to evade anti-cancer therapies?

Mutations in oncogenes and tumour suppressor genes are often observed in cancer, but with the advent of next generation sequencing researchers also realised that many other classes of proteins are frequently mutated, one of the of the most abundant being chromatin-associated proteins. In mammalian cells chromatin (complex between DNA a histone proteins) is the substrate for the complex process of transcription, involving polymerases, transcription factors and epigenetic modifiers. Another critical class of proteins required for facilitating transcription are chromatin remodelling factors. Although remodellers are often mutated in cancer¹, we do not understand why there is a strong selective pressure, to maintain these mutations, or the underlying molecular mechanisms that are being perturbed in the cell. Recently we have shown that transcriptionally active genes are surrounded by a nuclear gel, comprised of protein and RNA². We hypothesise that the nuclear gel provides a platform or framework for regulating chromatin-remodelling protein function. In this project we will test this hypothesis by perturbing proteins important for forming the nuclear gel and looking at the consequences on chromatin remodelling protein function, secondly, we will degrade chromatin remodelling machines in the presence or absence of the nuclear gel to understand how this influences transcription. Finally, we will ask why mutations in remodelling machines provide a selective advantage for cancer cells and whether these are important for mis-regulating gene expression programmes, altering transcriptional heterogeneity. Together this will provide new insight into how cells can adapt their transcription programmes to become resistant to anti-cancer therapies³.

1. Mittal, P., and Roberts, C.W.M. (2020). The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol 17, 435–448. https://doi.org/10.1038/s41571-020-0357-3.
2. Marenda, M., Michieletto, D., Czapiewski, R., Stocks, J., Winterbourne, S.M., Miles, J., Fleming, O.C.A., Lazarova, E., Chiang, M., Grimes, G.R., et al. (2024). Nuclear RNA forms an interconnected network of transcription-dependent and tunable microgels. bioRxiv. https://doi.org/10.1101/2024.06.16.599208.
3. França, G.S., Baron, M., King, B.R., Bossowski, J.P., Bjornberg, A., Pour, M., Rao, A., Patel, A.S., Misirlioglu, S., Barkley, D., et al. (2024). Cellular adaptation to cancer therapy along a resistance continuum. Nature 631, 876–883. https://doi.org/10.1038/s41586-024-07690-9.
4. Marenda, M., Lazarova, E., van de Linde, S., Gilbert, N., and Michieletto, D. (2021). Parameter-free molecular super-structures quantification in single-molecule localization microscopy. J Cell Biol 220. https://doi.org/10.1083/jcb.202010003.