Professor Bertie Göttgens
Network control of normal and leukaemic blood stem cells
Laboratory: Cambridge Institute for Medical Research, Cambridge Biomedical Campus
Departmental Affiliation: Haematology
Bertie Göttgens graduated from Tübingen University in 1992 with a degree in biochemistry. He received his DPhil in biological sciences from the University of Oxford in 1994 and then proceeded to a post-doc position in the Department of Haematology, University of Cambridge, between 1994-2001.
Between 2002-2007 he was a Leukaemia Research Fund Lecturer in the Department of Haematology, Cambridge. He was then a University Lecturer, and subsequently a Reader in Haematology, between 2007-2011.
Since October 2011, Bertie has been Professor of Molecular Haematology, University of Cambridge.
MRC, Wellcome, Leukaemia and Lymphoma Society, Bloodwise, BBSRC, Cancer Research UK, GSK, NIH MS Society, Autolus
Reconstruction of differentiation trajectories from single cell gene expression profiles provides unprecedented insights into the dynamic processes that drive blood stem cell differentiation. The diagram on the left shows putative differentiation trajectories of a haematopoietic stem cell (HSC) into Megakaryocyte-Erythroid Progenitors (MEP) or Lymphoid-primed Multi Potential Progenitors (LMPP). The diagram on the right shows a diffusion map representation of single cell expression profiles generated from primary blood stem and progenitor cells, with HSCs, MEPs and LMPPs highlighted using the same colour scheme as the left hand panel.
The Göttgens group uses a combination of experimental and computational approaches to study how transcription factor networks control the function of blood stem cells and how mutations that perturb such networks cause leukaemia. This integrated approach has resulted in the discovery of new combinatorial interactions between key blood stem cell regulators, as well as experimentally validated computational models for blood stem cells. Current research focuses on (i) single cell genomics of early blood development, (ii) computer models to chart the transcriptional landscape of blood stem and progenitor cell differentiation, (iii) transcriptional consequences of leukaemogenic mutations in leukaemia stem/progenitor cells, and (iv) molecular characterisation of human blood stem/progenitor cell populations used in cell and gene therapy protocols.
Silvia Basilico, Fernando Calero, Joakim Dahlin, Caroline Guibentif, Fiona Hamey, Rebecca Hannah, Wajid Jawaid, Sarah Kinston, Iwo Kucinski, Vasilis Ladopoulos, Winnie Lau, Chee Lim, Sonia Nestorowa, Blanca Pijuan Sala, Moosa Qureshi, Xiaonan Wang, Nicola Wilson.
Reconstructing differentiation from single cell expression profiles: Single cell expression profiling of a dynamic system can be used to capture expression states that represent putative differentiation trajectories. This gif shows a diffusion map representation of single cell RNA-Seq data for 1,600 single blood stem and progenitor cells with a putative differentiation trajectory that connects a sequence of cells that correspond to likely intermediate steps when a blood stem cell matures into a myeloid progenitor cell. The Göttgens group is using this approach to (i) define differentiation trajectories and lineage branchpoints, (ii) identify new putative regulators of blood cell differentiation, and (iii) infer gene regulatory networks that drive dynamic expression changes during stem cell differentiation.
Blood stem cells ensure the constant supply of new blood cells throughout a person’s lifetime. The normal function of blood stem cells critically depends on the fine tuning of which genes should be active at any given time. Moreover, a large number of leukaemias arise, when this fine balance of gene activities is disturbed. Through our research, we want to answer the following questions:
• What are the mechanisms that regulate gene activities to ensure normal blood stem cell function?
• Can we identify new strategies to treat leukaemia by reversing the disturbed balance of gene activities?
To answer these questions, we use a combination of experimental and computational approaches. This has allowed us to discover how individual regulatory genes are connected to form complex networks. Future work will investigate how perturbation of these complex networks can cause leukaemia.
- Scialdone A., Tanaka Y., Jawaid W., Moignard V., Wilson N.K., Macaulay I.C., Marioni J.C., Göttgens B. (2016). Resolving Early Mesoderm Diversification through Single Cell Expression Profiling Nature 535 (7611): 289-293
- Wilson NK, Kent DK, Buettner F, Shehata M, Macaulay IC, Calero-Nieto FJ, Sánchez Castillo M, Oedekoven CA, Diamanti E, Schulte R, Ponting CP, Voet T, Caldas C, Stingl J, Green AR, Theis FJ, Göttgens B. (2015). Combined single cell functional and gene expression analysis resolves heterogeneity within stem cell populations Cell Stem Cell 16(6): 712-724. PMCID:PMC4460190
- Moignard V, Woodhouse S, Haghverdi L, Lilly AJ, Tanaka Y, Wilkinson AC, Buettner F, Macaulay IC, Jawaid W, Diamanti E, Nishikawa S, Piterman N, Kouskoff V, Theis FJ, Fisher J, Göttgens B. (2015). Decoding the Regulatory Network for Blood Development from Single-Cell Gene Expression Measurements. Nat Biotech 33(3): 269-276. PMCID:PMC4374163
- Moignard V, Macaulay IC, Swiers G, Buettner F, Schütte J, Calero-Nieto FJ, Kinston S, Joshi A, Hannah R, Theis FJ, Jacobsen SE, de Bruijn MFT, Göttgens B. (2013) Characterisation of transcriptional networks in blood stem and progenitor cells using high-throughput single cell gene expression analysis. Nature Cell Biology 15: 363-372. PMCID:PMC3796878
- 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., Göttgens B. (2010) Combinatorial Transcriptional Control in Blood Stem/Progenitor Cells: Genome-wide Analysis of ten major Transcriptional Regulators Cell Stem Cell 74): 532-544