1. Establishment of the Haematopoietic Transcriptional Programme: From Systems Approaches to Molecular Mechanisms (together with B.Göttgens, Cambridge; G.Lacaud and V.Kouskoff, Manchester; D.Westhead, Leeds). BBSRC LoLa grant.
Postdocs: Monika Lichtinger, Nadine Obier. Technician: Laura Noailles. BBSRC student: Liam Redgrave
This project studies how the ordered interplay of transcription factors and specific chromatin states leads to the stable expression of lineage specific genetic programs. We use haemopoiesis as a model to identify the molecular mechanisms and dynamics of cell differentiation in a system-wide fashion. To this end we have formed a consortium consisting of experimental researchers and computational biologists to study haemopoietic development as particularly powerful system for the reconstruction of dynamic and global models of the molecular interactions governing an entire developmental pathway.
2. Mechanistic insights into the interplay between transcription factors and the epigenetic regulatory machinery in normal and leukaemic cells (together with Peter Cockerill). Leukemia Lymphoma Research Specialist Programme.
Postdocs: Anetta Ptasinska, Pierre Cauchy, So Yeon Kwon, Joaquin Zacarias, Maria Rosaria Imparato. PhD student: Anna Pickin. Collaborators: Olaf Heidenreich, University of Newcastle, Dan Tenen, Harvard Stem Cell Institute and National University of Singapore, David Westhead, University of Leeds.
In this program, we examine the molecular mechanisms underlying how normal and aberrant leukaemic transcription factors interact with the epigenetic regulatory machinery, reprogram the epigenetic landscape of normal human precursor cells and initiate the vast deregulation phenomena that we observe in malignant cells. We are also developing methods and computational tools that will allow us to model how the human epigenome swings back to normal, once we eliminate specific leukaemia-initiating oncogenes and/or block aberrant signalling through therapy.
3. The role of the transcription factor Sp1 in embryonic macrophage development. MRC.
Postdocs: Jane Gilmour, Salam Assi, in collaboration with Sjaak Philipsen, Erasmus University Rotterdam, and David Westhead, University of Leeds.
Macrophages fulfil multiple important functions in the mammalian organism and each macrophage type is tailored to specific functions within the tissues where they reside. Besides their function in the innate immune system, they also have other roles. These functions are particularly important during embryonic development where phagocytes are involved in tissue remodeling via the removal of cells undergoing programmed cell death. Using the differentiation of mouse ES cells as a model, we have recently demonstrated that embryonic macrophages are uniquely dependent on the presence of the transcription factor Sp1. This project studies the molecular basis of this finding.
4. Mechanistic insights into the deregulation of haematopoietic development by mutated forms of the RUNX1 transcription factor. Kay Kendall Leukaemia Fund.
Postdoc: Regha Kakkad, in collaboration with Georges Lacaud, Paterson Institute of Cancer Research, Manchester
The transcription factor RUNX1 is crucial for the establishment of haemopoiesis and mutation of this gene plays an important role in myeloid leukemia. However, little is known about the mechanistic details of how mutant versions of RUNX1 subvert normal haemopoietic development and counteract normal RUNX1 activity. Using the differentiation of mouse embryonic stem (ES) cells as model we address this question.
5. Geneome-wide maps of transcription factor binding in the human epigenome.
PhD student: Jason Piper, in collaboration with Sascha Ott, Systems Biology Institute, University of Warwick.
In this project we are employing nuclease digestion followed by high-throughput sequencing at high read depth to probe the chromatin fine structure of normal and malignant cells. This tells us how the epigenetic landscape differs between normal and cancer cells, and which transcription factor biding sites are occupied and which ones are not.
6. Consequences of Pax5 deregulation in acute myeloid leukaemia.
PhD student: Debleena Ray. Leukemia Lymphoma Research Gordon Piller student, together with Anetta Ptasinska, So Yeon Kwon and Olaf Heidenreich, University of Newcastle.
The master regulator of B cell development PAX5 is aberrantly expressed in a specific type of acute myeloid leukaemia carrying the t(8;21) translocation. The expression of this factor is one of the reasons why differentiation of cells is blocked in these cells. This project studies this gene locus in detail to determines why this is the case. Our research has uncovered that this aberrant activation is governed by the interplay of polycomb complexes and aberrant signalling.
7. Mechanistic insights into CpG island promoter regulation by the histone methyltransferase Mll2. EU Framework 6 studentship
PhD student: Vasileios Ladopoulos, in collaboration with Francis Stewart, University of Dresden and Arthur Riggs, Beckman Institute of City of Hope
Mll2 is a H3K4 specific histone methyltransferase which is vital for normal embryonic development in the mouse. In this project we conduct an in depth analysis of the molecular mechanism by which MLL2 regulates CpG island promoters.