Professor Constanze Bonifer

Professor Constanze Bonifer

Institute of Cancer and Genomic Sciences
Chair of Experimental Haematology

Contact details

Address
Institute of Cancer and Genomic Sciences
IBR
College of Medical and Dental Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

Constanze Bonifer is Chair of Experimental Haematology at the Institute of Cancer and Genomic Sciences (ICGS), University of Birmingham, and is Director of the Birmingham Centre of Genome Biology. In their work, they 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. It is known from genetic studies that chromatin modification complexes play essential roles in all phases of the development of multicellular organisms and that transcription factors bring these epigenetic regulatory proteins to specific genes.

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. To this end, the Bonifer lab employs genome-wide methods such as ChIP-sequencing and DNaseI-sequencing to generate such data. They collaborate with computational biologists to reconstruct models of the molecular interactions driving blood cell development. However, they 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. The results of these 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.

Qualifications

  • 1995 Habilitation in Molecular Biology and Genetics, University of Freiburg, Germany
  • 1985 PhD in Natural Sciences 1985, University of Heidelberg, Germany

 

Biography

Constanze Bonifer studied Biology at the University of Cologne, Germany and graduated 1980 with a first class degree in Biochemistry, Chemistry and Genetics. She then went on to do a PhD in Biochemistry and Molecular Biology, first at the University of Cologne, then at the Centre for Molecular Biology, University of Heidelberg.

This was followed by Postdoctoral training periods at the Karolinska Institute, Stockholm, and the National Institute for Medical Research in London where she started to work on gene regulation.

1990 she became Assistant Professor and independent group leader at University of Freiburg, Germany, where she worked on gene regulation in the hematopoietic system.

1997 she went back to the UK and became a group leader at the Molecular Medicine Unit, University of Leeds, where she started to work not only on basic mechanisms controlling blood cell development, but also on epigenetic mechanisms controlling leukemogenesis.

She became a Reader in 2000, a Professor in 2003 and in 2004 became a full Professor and Chair of Experimental Haematology. In 2006 she was appointed Head of Section of Experimental Haematology at the Leeds Institute of Molecular Medicine.

Since August 2011, Constanze is in Birmingham as Chair of Experimental Haematology and leads the Section of Genome Structure and Function in the Institute of Cancer and Genomic Sciences.  

Constanze holds a programme grant from Bloodwise, as well as grants from the BBSRC, the MRC and the Kay Kendall Leukaemia fund, together with several studentships.

Teaching

Professor Bonifer provides mini-projects and master classes, and gives lectures on haemopoiesis and leukaemia in the MBChB Clinical Sciences Haematology module, the MRes in Cancer Sciences and the Genomic Medicine Masters programme.

Postgraduate supervision

Constanze has currently four PhD students as well as Master's students and is interested in supervising postgraduate research in the following areas:

  • Basic mechanisms controlling blood cell development
  • Molecular mechanisms regulating aberrant gene regulation in leukaemia

Research

The main research interest of the Bonifer lab is to study the mechanism of cell fate decisions in the haematopoietic system at the level of gene regulation. A number of diseases such as leukaemia affect blood cell development, an understanding of the molecular basis of hematopoietic cell differentiation is therefore of utmost importance for the development of new therapeutic strategies. We want to understand how different genetic programs are activated and silenced at specific stages of hematopoiesis and which factors are involved in this process.

Current research

A large body of evidence from genetic studies demonstrates that  transcription factors interacting with the chromatin modification machinery play essential roles in all phases of the development of multicellular organisms. As individual genes, these epigenetic regulatory proteins influence the transcriptional status, the chromatin structure and the spectrum of biochemical tags attached to individual chromatin components. Such epigenetic events underlay all cell fate decisions and are the basis for the progressive restriction in the developmental potential of all stem cell types. They are also responsible for aberrant cell differentiation in leukaemia. However, very little is known about the molecular details of these processes.

To address the issue of cell specification and cell lineage restriction at the molecular level we study the regulation of chromatin structure of genes expressed in the myeloid lineage of the hematopoietic system. We are identifying the order of events taking place during the developmentally controlled activation of genes and we study how genes are epigenetically silenced. Our research has shown that even before the onset of gene expression and stable transcription factor binding, chromatin of lineage specific genes is partially accessible and transiently bound by transcription factors, and that the silencing of genes during the differentiation of alternative lineages occurs in defined and distinct steps. We also have gained insights in the epigenetic consequences of the action of nuclear oncoproteins involved in leukaemia.

To examine the full complexity of regulatory interactions at the genome, we perform research along the following lines:

research along the following lines:

1) We study the role of chromatin structure components and specific transcription factors in the activation of genes specific for a given differentiation pathway.

2) We are using the differentiation of mouse and human embryonic stem cells into hematopoietic cells as models to gain insights into how transcription factors program chromatin. Our work has identified a core transcriptional network driving hematopoietic specification (Goode et al., 2016) and made a first in-road into how signalling responsive transcripition factors shape the epgenome (Obier et al., Development 2016; Gilmour et al., 2014, 2018). We are also using these systems to gain insights into the first genomic events after the expression of specific oncogenes

3) We are analyzing the impact of mutations in transcription factor and chromatin modifier genes on blood cell development in a system-wide fashion using Next Generation Sequencing approaches such as DNase-Seq, ATAC-Seq, ChIP-Seq and  RNA-Seq (bulk and single cell).

4) It is now absolutely clear that cancer is disease of aberrant gene regulation. A large part of our research is therefore devoted to the question of how the epigenome is reprogrammed in leukaemia (Ptasinska et al., 2014; Cauchy et al., 2015; Assi et al., 2019). Jointly with the lab of Prof Peter Cockerill, we investigate aberrant human blood cell differentiation processes in a system-wide fashion using multi-omics approaches. The aim of these studies is to identify gene tumour specific gene regulatory networks and find those components that are required for tumour development and maintenance.  (https://www.birmingham.ac.uk/university/colleges/mds/news/2018/11/bonifer-leukaemia.aspx)

Future plans:

One of the great challenges for future biological research will be to understand in a system-wide fashion how cell fate decisions are regulated in normal cells and how they are subverted in abnormal cells. We know very little about hierarchical relationships between different network states or how metastable states are established and eventually altered. We do not know how the ordered interplay of transcription factors and specific chromatin states eventually leads to the stable expression of lineage specific genetic programs. We are collaborating with computational biologists to reconstruct dynamic and global models of the molecular interactions governing blood cell development.

Such information is vital for our translational research program. Interactions between transcription factors and epigenetic regulatory proteins are at the heart of normal and malignant cell differentiation processes and we consider our basic research as a necessary prerequisite to our ongoing efforts to understand and target primary and secondary events in tumour formation: in the nucleus of a cell.

Bonifer is the Director of the Birmingham Centre for Genome Biology and a member of the Birmingham CRUK Centre

Other activities

Constanze Bonifer is the Director of the Birmingham Centre for Genome Biology, a member of the International Society of Experimental Haematology (ISEH) and a member of the Editorial Board of Experimental Haematology. 

She was the co-organizer of Cancer Epigenetics conference, May 2013 and the Birmingham Centre for Genome Biology meetings on Genome Biology, 2016 - 2019. 

Professor Bonifer is a frequent reviewer for international journals (Cell, EMBO J, Genes & Development, J. Experimental Medicine, Nature Genetics, Blood, Stem Cells, Leukemia, Mol. Cell. Biology, J. Biol. Chemistry, PNAS, Human Molecular Genetics, Nucleic Acids Research, Gene, Genome Biology), and also reviews national and international grant proposals and as member of site visit panels. 

Between 2009 and 2012 she was a member of the Bloodwise Career and Fellowship panel, between 2012 and 2014 she was Vice-Chair of Committee C of the BBSRC and she is currently serving for the non-clinical career development fellowship panel for the MRC.

Publications

Constanze Bonifer currently lists 134 publications in PubMed. Here are the most important peer reviewed publications from the last five years:

Edginton-White B, Cauchy P, Assi SA, Hartmann S, Riggs AG, Mathas S, Cockerill PN, Bonifer C (2019). Global long terminal repeat activation participates in establishing the unique gene expression programme of classical Hodgkin lymphoma. Leukemia. 2018 Dec 13. doi: 10.1038/s41375-018-0311-x

Assi SA, Imperato MR, Coleman DJL, Pickin A, Potluri S, Ptasinska A, Chin PS, Blair H, Cauchy P, James SR, Zacarias-Cabeza J, Gilding LN, Beggs A, Clokie S, Loke JC, Jenkin P, Uddin A, Delwel R, Richards SJ, Raghavan M, Griffiths MJ, Heidenreich O, Cockerill PN, Bonifer C. (2019) Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nature Genetics. 51(1):151-162

Gilmour, J., Assi, S.A., Obier, N., and Bonifer, C. The Co-operation of RUNX1 with LDB1, CDK9 and BRD4 Drives Transcription Factor Complex Relocation During Haematopoietic Specification. Revision submitted to Scientific Reports 8(1):10410 

de Boer B, Prick J, Pruis MG, Keane P, Imperato MR, Jaques J, Brouwers-Vos AZ, Hogeling SM, Woolthuis CM, Nijk MT, Diepstra A, Wandinger S, Versele M, Attar RM, Cockerill PN, Huls G, Vellenga E, Mulder AB, Bonifer C*, Schuringa JJ (*Senior author). Prospective Isolation and Characterization of Genetically and Functionally Distinct AML Subclones. Cancer Cell 34(4):674-689. 

Assi SA, Imperato MR, Coleman DJL, Pickin A, Potluri S, Ptasinska A, Chin PS, Blair H, Cauchy P, James SR, Zacarias-Cabeza J, Gilding LN, Beggs A, Clokie S, Loke JC, Jenkin P, Uddin A, Delwel R, Richards SJ, Raghavan M, Griffiths MJ, Heidenreich O, Cockerill PN, Bonifer C. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nature Genetics. doi: 10.1038/s41588-018-0270-1. [Epub ahead of print] 

Gilmour, J., Assi, S.A., Obier, N., and Bonifer, C. The Co-operation of RUNX1 with LDB1, CDK9 and BRD4 Drives Transcription Factor Complex Relocation During Haematopoietic Specification. Scientific Reports 8(1):10410. 

Martinez-Soria N, McKenzie L, Draper J, Ptasinska A, Issa H, Potluri S, Blair HJ, Pickin A, Isa A, Chin PS, Tirtakusuma R, Coleman D, Nakjang S, Assi S, Forster V, Reza M, Law E, Berry P, Mueller D, Elder A, Bomken SN, Pal D, Allan JM, Veal GJ, Cockerill PN, Wichmann C, Vormoor J, Lacaud G, Bonifer C*, Heidenreich O*. (*Joint corr. Authors). An Aberrant Transcription Factor Corrupts the Cell Cycle to Drive Leukemic Transformation. Cancer Cell 34(4):626-642.e8. 

Hull MA, Cuthbert RJ, Ko CWS, Scott DJ, Cartwright EJ, Hawcroft G, Perry SL, Ingram N, Carr IM, Markham AF, Bonifer C, Coletta PL. Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc Min/+ mouse model of intestinal tumorigenesis. Sci Rep. 2017 Jul 20;7(1):6074. 

Loke, J.T, Chin,P.S.,  Assi, S.A, Ptasinska,A.,  Imperato, M.R., Cockerill, P.N. and Bonifer, C. C/EBPα overrides epigenetic reprogramming by oncogenic transcription factors in acute myeloid leukemia. Blood Adv. 2018 Feb 13;2(3):271-284 

Shan Lin, Anetta Ptasinska, Xiaoting Chen, Mahesh Shretha, Salam A. Assi, Paulynn S. Chin, Maria R. Imperato, Bruce Aronow, Jingsong Zhang, Matthew T. Weirauch, Constanze Bonifer, and James C. Mulloy. AML1-ETO-induced FOXO1 activates a self-renewal program in pre-leukemia stem cells. Blood. 2017 Sep 7;130(10):1213-1222. 

Loke, J.T, Assi, S.A, Imperato, M.R., Ptasinska,A., Cauchy,P., Grabovska,Y., Martinez Soria, N., Raghavan, M., Delwel, H.R., Cockerill, P.N., Heidenreich, O., and Bonifer, C (2017). RUNX1-ETO and RUNX1-EVI1 differentially re-program the chromatin landscape in t(8;21) and t(3;21) AML. Cell Reports. 19(8):1654-1668. With press release. 

Bonifer C, and Cockerill PN. Chromatin priming of genes in development: Concepts, mechanisms and consequences. Bonifer Exp Hematol. 2017 May; 49:1-8. Epub 2017 Feb 7. Review. 

Obier, N. and Bonifer, C.. Chromatin programming by developmentally regulated transcription factors: lessons from studying hematopoietic specification and differentiation. FEBS Lett. 2016 Nov;590(22):4105-4115. 

Shan Lin, Roger T. Luo, Anetta Ptasinska, Mark Wunderlich, Toshihiko Imamura, Joseph J. Kaberlein, Ahmad Rayes, Mark J Althoff, John Anastasi, Maureen M. O’Brien, Constanze Bonifer, James C. Mulloy and Michael J. Thirman (2016) Instructive role of MLL fusion proteins revealed by a faithful model of t(4;11) proB acute lymphoblastic leukemia. Cancer Cell;30(5):737-749. With accompanying editorial. 

Nadine Obier, Pierre Cauchy, Salam A. Assi, Jane Gilmour, Michael Lie-A-Ling, Monika Lichtinger, Maarten Hoogenkamp, Laura Noailles, Peter N. Cockerill, Georges Lacaud, Valerie Kouskoff and Constanze Bonifer (2016). Cooperative binding of AP-1 and TEAD4 regulates the balance between vascular smooth muscle and hemogenic cell fate. Development;143(23):4324-4340 (highlighted article) 

Illendula, A., Gilmour,J., Grembecka,J., Sesha Srimath Tirumala,V., Boulton, A., Kuntimaddi, A., Schmidt, C., Wang, L., Pullikan, J.A., Zong, H., Parlak, M., Kuscu, C., Pickin, A., Zhou, Y., Gao, Y., Mishra, L., Adli, M., Castilla, L.H., Rajewski, R.A., Janes, K.A., Guzman, M.L., Bonifer, C. and Bushweller, J.H. (2016). Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers. eBiomedicine. ePub April 2016. 

Goode DK, Obier N, Vijayabaskar MS, Lie-A-Ling M, Lilly AJ, Hannah R, Lichtinger M, Batta K, Florkowska M, Patel R, Challinor M, Wallace K, Gilmour J, Assi SA, Cauchy P, Hoogenkamp M, Westhead DR, Lacaud G, Kouskoff V, Göttgens B, Bonifer C. (2016). Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation.  Dev Cell. 36(5):572-87 

Bonifer, C. and Cockerill, P.N. (2016) Chromatin Structure Profiling Identifies Crucial Regulators of Tumor Maintenance. Trends in Cancer 1, 157 - 158 

Jason Piper, Salam A. Assi, Pierre Cauchy, Christophe Ladroue, Peter N. Cockerill*, Constanze Bonifer*, Sascha Ott,* (*Joint corr. Authors). (2015). Wellington-bootstrap: Differential DNase-seq footprinting identifies cell-type determining transcription factors. BMC Genomics. 16; 1000 

Susumu Goyama*, Janet Schibler, Anjelika Gasilina, Shan Lin, Kevin A. Link, Mahesh Shrestha, Jianjun Chen, Susan P. Whitman Clara D. Bloomfield, Salam Assi, Anetta Ptasinska, Olaf Heidenreich, Constanze Bonifer, Nicolas Nassar, James C. Mulloy (2015). UBASH3B (Sts-1)-CBL axis regulates myeloid proliferation in human AML1-ETO-induced leukemia. Leukemia 30, 728 – 739 

van Oevelen C, Collombet S, Vicent G, Hoogenkamp M, Lepoivre C, Badeaux A, Bussmann L, Sardina JL, Thieffry D, Beato M, Shi Y, Bonifer C, Graf T. C/EBPα Activates Pre-existing and De Novo Macrophage Enhancers during Induced Pre-B Cell Transdifferentiation and Myelopoiesis. Stem Cell Reports. 2015 Aug 11;5(2):232-47. 

Cauchy P, James SR, Zacarias-Cabeza J, Ptasinska A, Imperato MR, Assi SA, Piper J, Canestraro M, Hoogenkamp M, Raghavan M, Loke J, Akiki S, Clokie SJ, Richards SJ, Westhead DR, Griffiths MJ, Ott S, Bonifer C*, Cockerill PN* (joint corr. Authors). Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature. Cell Rep. 2015 Aug 4;12(5):821-36. 

Regha K, Assi SA, Tsoulaki O, Gilmour J, Lacaud G, Bonifer C. (2014) Developmental-stage-dependent transcriptional response to leukaemic oncogene expression. Nature Commun. 2015 May 28;6:7203. 

Kreher S, Bouhlel MA, Cauchy P, Lamprecht B, Li S, Grau M, Hummel F, Köchert K, Anagnostopoulos I, Jöhrens K, Hummel M, Hiscott J, Wenzel SS, Lenz P, Schneider M, Küppers R, Scheidereit C, Giefing M, Siebert R, Rajewsky K, Lenz G, Cockerill PN, Janz M, Dörken B, Bonifer C*, Mathas S* (joint corr. authors). Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4513-22. 

Ptasinska A, Assi SA, Martinez-Soria N, Imperato MR, Piper J, Cauchy P, Pickin A, James SR, Hoogenkamp M, Williamson D, Wu M, Tenen DG, Ott S, Westhead DR, Cockerill PN, Heidenreich O, Bonifer C. Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal. Cell Reports. 2014 Sep 25;8(6):1974-88. 

Lie-A-Ling M, Marinopoulou E, Li Y, Patel R, Stefanska M, Bonifer C, Miller C, Kouskoff V, Lacaud G. RUNX1 positively regulates a cell adhesion and migration program in murine hemogenic endothelium prior to blood emergence. Blood. 2014 Sep 11;124(11):e11-20. 

Gilmour, J., Assi, S.A., Jaegle, U., Kulu, D., van der Werken, H., Clarke, D., Westhead, D.R., Philipsen, S. and Bonifer,C. (2014) A crucial role of the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification. Development. Jun;141(12):2391-401 

Piper, J., Elze. MC., Cauchy, P., Cockerill, P.N*., Bonifer,C*., Ott, S*. (*joint corr authors) Wellington: A novel method for the accurate identification of digital genomic footprints from DNase-seq data. Nucleic Acids Res. 2013 Nov;41(21):e201. 

Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, Di Ruscio 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. (2013). Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia. Cancer Cell. 24(5):575-88. 

Ray, D., Kwon, S.Y., Tagoh, H., Heidenreich, O., Ptasinska, A. and Bonifer, C (2013). Lineage inappropriate PAX5 expression in t(8;21) acute myeloid leukemia requires signalling mediated abrogation of polycomb repression. Blood. 122(5):759-69 

The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter. Ladopoulos, V., Hofemeister, H., Hoogenkamp, M., Riggs, A.D. Stewart, A.F. and Bonifer, C (2013). Mol Cell Biol. 33(7):1383-1393 

The function of the conserved regulatory element within the first intron of the mammalian Csf1r locus. Sauter, K.A., Bouhlel, M.A., O’Neala, J.  1, Sester, D.P., Tagoh, H. Ingram, R.M., Pridansa, C., Bonifer, C.+, and Hume, D.A. + (2013) (joint corr. Authors). PlosOne.;8(1):e54935 

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 hematopoietic development. EMBO J.  31:4318-33

Book

Bonifer C, Cockerill PN (eds) Transcriptional and Epigenetic Mechanisms Regulating Normal and Aberrant Blood Cell Development. Epigenetics and Human Health, Springer, Heidelberg, 2014. ISBN 978-3-642-45198-0

View all publications in research portal