Research at LICR Oxford
- Prof. Xin Lu
- Prof. Colin Goding
- Prof. Peter Ratcliffe
- Dr Gareth Bond
- Dr John Christianson
- Dr Sarah De Val
- Dr Skirmantas Kriaucionis
- Dr Panagis Filippakopoulos
From stem cells to cancer: deciphering the Mitf code
Mitf and the DNA damage response
T-box factors and regulation of senescence
T-box factors and epigenetic inheritance
Understanding how promoter architecture dictates requirements for transcription co-factors
The goals of our research are to understand how signalling and transcription control phenotype switching and senescence in melanoma, and to develop markers of epigenetic architecture to monitor the clinical impact of anti-cancer therapies.
Over the past five years, since we first uncovered a melanocyte-specific cell cycle regulator, we have been examining the role and regulation of a transcription factor cascade that controls melanoma differentiation, proliferation and senescence. The results have enabled us to elaborate a model in which tumour heterogeneity is driven by reversible microenvironment-mediated cell fate switches, between three populations of cells circumscribed by their differentiated, proliferative or invasive/stem cell-like phenotypes. In particular, cell identity is controlled by the levels and post-translational modifications of the Mitf transcription factor, which is in turn regulated by Brn-2, while senescence is bypassed by the activity of the Tbx2 and Tbx3 factors. We have also identified a novel class of regulatory proteins, termed promoter education factors, which are required for the function of classical transcription activators and provide a transcription memory function by mediating the post-transcriptional interaction of a specific gene with nuclear pore components. Further work has raised the possibility that activation of transcription represents the arrest and reversal of an anti-sense RNA Polymerase, by activator-recruited basal transcription machinery.
Future work will aim to balance and combine our interest in the basic mechanisms of gene regulation, with our desire to translate our results on melanoma to the clinic. We therefore aim to: 1) understand how signalling pathways are interpreted by transcription factors to drive phenotype switching and suppress senescence in melanoma; 2) decipher the molecular events underlying transcriptional memory in melanoma; and 3) use epigenetic architecture to define and monitor melanoma subpopulations in a clinical setting.
Delmas, V., Beermann, F., Martinozzi, S., Carreira, S., Ackermann, A., Kumasaka, M., Denat, L., Goodall, J., Demirkan, N., Goding, C.R., and Larue L. (2007) b-catenin suppresses p16INK4a expression to bypass senescence and predispose to melanoma. Genes & Dev 21, 2923-2935.
Carreira, S., Goodall, J. Denat, L., Rodriguez, M., Nuciforo, P, Hoek, K.S., Testori, A., Larue, L. and Goding, C.R. (2006) Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes & Dev 20, 3426-3439.
Carreira, S., Goodall, J., Aksan, I., La Rocca, S.A., Galibert, M.-D., Denat, L., Larue, L. and Goding, C.R. (2005) Mitf cooperates with Rb1 and activates p21Cip1expression to regulate cell cycle progression. Nature 433, 764-769.
Martinez-Campa, C, Politis, P., Moreau, J.-L., Kent, N., Goodall, J., Mellor, J. and Goding C.R. (2004) Precise nucleosome positioning and the TATA box dictate requirements for the histone H4 tail and the bromo-domain factor Bdf1. Molecular Cell 15, 69-81.
Vance, K.W., Carreira, S. Brosch, G. and Goding C.R. (2005) Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer Res. 65, 2260-2268.
Moreau, J-L., Lee, M., Mahachi, M., Vary, J., Mellor, J., Tsukiyama, T., and Goding, C.R. (2003) Regulated displacement of TBP from the PHO8 promoter in vivo requires Cbf1 and the Isw1 chromatin remodeling complex. Molecular Cell 11,1609-1620.