Transcriptional control of normal and leukaemic blood stem cells
The long term research goal of the Göttgens group is to decipher the molecular hierarchy of regulatory networks responsible for blood stem cell and endothelial development. To this end, the group uses complementary state-of-the-art approaches including embryonic stem cell and transgenic assays, bioinformatics, high throughput sequencing, single cell expression profiling and mathematical modelling. The cumulative output of more than 50 research papers over the last 5 years has been the development of the most comprehensive network model for any adult stem cell type with over 40 transcription factors and more than 100 in vivo validated direct functional interactions.
This integrated approach has resulted in the discovery of previously unrecognised combinatorial interactions between key regulators of blood stem cells with important implications for the transcriptional control of stem cell development and differentiation.
The importance of transcriptional control in both normal and leukaemic cells is underlined by the large number of transcription factor genes that cause leukaemia when disrupted or mutated. Future work will address how transcriptional programmes are perturbed in specific subtypes of leukaemia and may thus open up new avenues for the development of targeted therapies.
Bertie Göttgens, whose lab is based in the CIMR, is a principal investigator of the Cambridge Stem Cell Institute (SCI) and will relocate to a new SCI building in 2018.
Moignard V., Woodhouse S., Haghverdi L., Lilly A.J., Tanaka Y., Wilkinson A.C., Buettner F., Macaulay I.C., Jawaid W., Diamanti E., Nishikawa S., Piterman N., Kouskoff V., Theis F.J., Fisher J. and Göttgens B. Decoding the Regulatory Network for Blood Development from Single-Cell Gene Expression Measurements. Nature Biotech. 33, 269-276 (2015).
Moignard, V., Macaulay, I.C., Swiers, G., Buettner ,F., Schütte, J., Calero-Nieto, F.J., Kinston, S., Joshi, A., Hannah, R., Theis, F.J., Jacobsen, S.E., de Bruijn, M.F.T. and Göttgens, B. Characterisation of transcriptional networks in blood stem and progenitor cells using high-throughput single cell gene expression analysis. Nature Cell Biol. 15, 363–372 (2013).
Ruau, D., Ng, F.S.L., Wilson, N.K., Hannah, R., Diamanti, E., Lombard, P., Woodhouse, S. and Göttgens, B. Building an ENCODE style data compendium on a shoestring. Nature Methods 10, 926 (2013).
Griffiths, D.S., Li, J., Dawson, M.A., Trotter, M., Cheng, Y.-H., Smith, A.M., Mansfield, W., Liu, P., Kouzarides, T., Nichols, J., Bannister, A.J., Green, A.R. and Göttgens, B. LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. Nature Cell Biol. 13, 13–21 (2011).
Wilson, N.K., Foster, S.D., Wang, X., Knezevic, K., Schütte, J., Kaimakis, P., Chilarska, P., Kinston, S., Ouwehand, W.H., Dzierzak, E., Pimanda, J.E., de Bruijn, M.F. and Göttgens, B. Combinatorial Transcriptional Control in Blood Stem/Progenitor Cells: Genome-wide Analysis of 10 major Transcriptional Regulators. Cell Stem Cell 7, 532–544 (2010).