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Transcriptional programming of chromatin in normal and malignant haematopoiesis

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  • Full or part time
    Prof C Bonifer
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

In our work, we address the question of how the regulators of transcription, the sequence-specific DNA binding proteins or transcription factors, interact with the chromatin template and change its structure. We know from genetic studies that chromatin modification complexes play essential roles in all phases of the development of multicellular organisms.
We also know that transcription factors bring these epigenetic regulatory proteins to specific genes. Together, they are responsible for the expression of different genes. Our research has shown that even the process of expressing one gene at the right time and in the right cell is a breathtakingly complex process that involves the coordinate action of hundreds of different molecules. We have also made progress in understanding how these intricately balanced processes are disturbed in leukaemia.
We have now taken these studies one step further. One of the great challenges for future biological and medical research will be to understand how all genes and all molecules in a cell work together to generate different cells that each express only one set of genes. This means that we will have to study all genes simultaneously. To this end, we employ sophisticated genome-wide methods such as ChIP-sequencing and DNaseI-sequencing to generate such data.
We also collaborate with computational biologists to reconstruct models of the molecular interactions driving blood cell development. However, we also study the global consequences of expression of aberrant transcription factors in form of nuclear oncogenes on how the epigenetic landscape is altered in leukaemic cells. The outcome of such studies will shed light on the complex deregulation processes that turn normal into leukaemic cells and will uncover novel therapeutic targets to combat a disease with a high death toll, in particular amongst the elderly.
The results of our experiments are therefore not only important for our understanding of how blood cells form, but are extremely important for how we may diagnose and treat patients in the future.

Funding Notes


References

References (optional; no more than 4/5 entries):
• Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, Diruscio A, Welner RS, Ebralidze A, Zhang J, Levantini E, Lefebvre V, Valk PJ, Delwel R, Hoogenkamp M, Nerlov C, Cammenga J, Saez B, Scadden DT, Bonifer C, Ye M, Tenen DG. Sox4 is a key oncogenic target in C/EBP? mutant acute myeloid leukemia. Cancer Cell. 2013; 24(5):575-88.
• Ray D, Kwon SY, Tagoh H, Heidenreich O, Ptasinska A, Bonifer C. Lineage-inappropriate PAX5 expression in t(8;21) acute myeloid leukemia requires signaling-mediated abrogation of polycomb repression. Blood. 2013; 122(5):759-69.
• Lichtinger, M., Ingram, R.M., Hannah, R., Clarke, D., Müller, D., Lie-A-Ling, M., Noailles, L., Zhang, P., Wu, M., Tenen, D.G., Assi, S., Westhead, D.R., Kouskoff, V., Lacaud, G., Göttgens, B., and Bonifer, C. (2012) RUNX1 reshapes the epigenetic landscape at the onset of haematopoietic development. EMBO J. In press.
• Ptasinska, A.; Assi, S.A., James, S.R.,Williamson, D.,Hoogenkamp, M., Mengchu, W., Care, M., McNeill, H., Cullen, M., Tooze, R., Tenen, D.G., Cockerill, P.N. Westhead, D.R.,Heidenreich, O. and Bonifer, C. (2012). Reversible genome-wide epigenetic reprogramming by the leukemia-initiating fusion protein RUNX1/ETO. Leukemia 26:1829-41
• Leddin, M., Perrod, C. , Hoogenkamp, M., Ghani, S., Ass, S., Heinz,S., Wilson, N.K., Follows, G., Schönheit,J., Vockentanz,L., Mosamam,A., Chen, W., Tenen, D.G., Westhead, D.R., Göttgens, B., Bonifer, C*. and Rosenbauer, F*. (2011) (*joint corr. authors). Two distinct auto-regulatory loops operate at the Pu.1 locus in B cells and myeloid cells. Blood. Mar 10;117(10):2827-38
• Lamprecht, B., Walter, K., Kreher, S., Kumar, R., Hummel, M., Lenze, D., Köchert, K., Bouhlel, M.A., Richter, J., Soler, E., Stadhouders, R., Jöhrens, C., Wurster, K.D., Callen, C., Harte, M.F., Giefing, M., Barlow, R., Stein, H., Anagnostopoulos, I., Janz, M., Cockerill, P.N., Siebert, R., Dörken, B., Bonifer, C.*, and Mathas, S.* (2010). (*Joint corresponding authors). De–repression of an endogenous long terminal repeat activates the CSF1R proto–oncogene in human lymphoma. Nature Medicine. 16, 571 – 579



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