“Cell cycle control plays a central role in maintaining adult stem cell pools and in decisions to adopt specific cell fates”
We are interested in the mechanisms that regulate gene expression as cells differentiate from early pluripotent stem cells and develop into specialized cell types. During this process cells go through bursts of proliferation to expand the pool of progenitors that give rise to fully differentiated cells. They can also exit the cell cycle and become quiescent, a process that is particularly important for maintaining numbers of self- renewing multipotent adult stem cells and protecting them from DNA damage. In contrast, pluripotent embryonic stem cells divide very rapidly, have a shortened G1 phase of the cell cycle and lack a quiescent stage.
We study how cell cycle regulation affects gene expression during differentiation of B and T cells and in a variety of stem cell models including ES cells. We are using these systems to investigate the roles of a number of proteins including the polycomb proteins and the Aurora B kinase in epigenetic regulation of the choice between proliferative and quiescent gene expression programmes in normal and cancerous cells.
The Aurora B kinase has diverse roles that include orchestrating mitosis and cytokinesis in proliferating cells and regulating gene expression in conjunction with polycomb proteins in quiescent lymphocytes. Left panels: Immunofluorescence analysis of cycling activated B cells. Aurora B (green) is localised to pericentromeric heterochromatin in mitotic cells. Right panel: Chip-seq analysis shows binding of Aurora B and the polycomb proteins, Ring1B and CBX7, to active promoters in quiescent resting B cells.
Sabbattini, P., Sjoberg, M., Nikic, S., Frangini, A., Holmqvist, P.-H. H., Kunowska, N., Carroll, T., Brookes, E., Arthur, S. J., Pombo, A., & Dillon, N. (2014). A H3K9/s10 methyl-phospho switch modulates polycomb and pol II binding at repressed genes during differentiation. Molecular Biology of the Cell.
Auner, H. W., Marie, A., Ward, T. H., Kraus, M., Milan, E., May, P., Chaidos, A., Driessen, C., Cenci, S., Dazzi, F., Rahemtulla, A., Apperley, J. F., Karadimitris, A., & Dillon, N. (2013). Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells. PLoS ONE, 8(9).
Frangini, A., Sjöberg, M., Roman-Trufero, M., Dharmalingam, G., Haberle, V., Bartke, T., Lenhard, B., Malumbres, M., Vidal, M., & Dillon, N. (2013). The aurora b kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes. Molecular Cell, 51(5), 647–661.
Dillon, N. (2012). Factor mediated gene priming in pluripotent stem cells sets the stage for lineage specification. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 34(3), 194–204.
Auner, H. W., Beham-Schmid, C., Dillon, N., & Sabbattini, P. (2010). The life-span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress. Blood, 116(18), 3445-55
Liber, D., Domaschenz, R., Holmqvist, P.-H. H., Mazzarella, L., Georgiou, A., Leleu, M., Fisher, A. G., Labosky, P. A., & Dillon, N. (2010). Epigenetic priming of a pre-B cell-specific enhancer through binding of sox2 and foxd3 at the ESC stage. Cell Stem Cell, 7(1), 114–126.
Dillon, N. (2008). The impact of gene location in the nucleus on transcriptional regulation. Developmental Cell, 15(2), 182–186.
Sabbattini, P., Canzonetta, C., Sjoberg, M., Nikic, S., Georgiou, A., Kemball-Cook, G., Auner, H. W., & Dillon, N. (2007). A novel role for the aurora b kinase in epigenetic marking of silent chromatin in differentiated postmitotic cells. The EMBO Journal, 26(22), 4657–4669.
Szutorisz, H., Georgiou, A., Tora, L., & Dillon, N. (2006). The proteasome restricts permissive transcription at tissue-specific gene loci in embryonic stem cells. Cell, 127(7), 1375–1388.