Transcriptional control of haematopoietic specification and differentiation

Our interests focus on the mechanisms that underlie blood formation and differentiation into mature blood cells (such as those fighting infection, involved in coagulation or in oxygen transport). Many inherited and acquired diseases are associated with anaemia and leukaemia in which production of certain types of blood cells is disrupted. Understanding these disorders depends on knowing how blood normally forms in the bone marrow and throughout development. Recently, there has been considerable accumulation of knowledge about the factors that direct formation of the blood. One such factor (called SCL, Stem Cell Leukaemia) plays several critical roles in this process. We plan to understand how this factor controls the formation of blood at a molecular level. Our main experimental model makes use of mouse embryonic stem (mES) cells that can reproduce the early steps of embryonic development in vitro (in a culture dish). We aim at understanding how a blood-specific protein complex forms, how it regulates the coordinated expression of the critical players involved in this pathway and how, when it is deregulated, it may lead to leukaemia and anaemia.

Understanding how stem cells are specified during embryonic development and how lineages differentiate to produce mature and specialised cells are central questions in biology and are of crucial interest to elucidate pathways involved in diseases. The main aim of this programme is to characterise some of the molecular mechanisms engaged by key regulators of blood development (such as SCL/Tal1), with a particular focus on the early stages of mesoderm patterning and haematopoietic specification. Functional identification of protein complexes and their nuclear targets combined with molecular characterisation of their mechanisms of action and structural biology approaches will give insights into genetic interactions and transcriptional networks critical in decision pathways. Using in vitro differentiation of mouse ES cells, mouse haematopoiesis and Xenopus embryos as experimental models, we will start building networks of genetic interactions at the heart of haematopoietic development. These approaches are instrumental for our understanding of how a haematopoietic stem cell-specific protein complex might form and how, when this process is deregulated, this leads to leukaemia. Moreover, this might help characterise the pathways leading to definitive haematopoiesis and HSCs from hES and iPS cells that remain poorly characterised. This is important if one wants to be able to produce HSCs in vitro for regenerative medicine purposes.