Abstract

Characterisation of the regulatory networks regulating stem cells will be vital to harness their full potential for both therapeutic and drug discovery applications. Our group has a long track record of studying transcriptional regulatory elements active in blood stem cells and provided the first molecular characterisation of any element active in adult stem cells. The group has also developed bioinformatic tools to identify functionally related regulatory elements and is thus defining key components of an emerging blood stem cell network currently composed of 15 transcription factors with over 40 experimentally verified connections. Within this network, we have identified a regulatory circuit made up of Gata2, Fli1 and Scl/Tal1 and their enhancers, Gata2-3, Fli1+12, and Scl+19. The three blood stem cell enhancers are bound by each of these transcription factors and thus form a fully connected triad. By performing quantitative measurements of the regulatory interactions within this network motif, we have been able to build a mathematical model describing the function of this regulatory circuit in blood stem cells. The Gata2/Fli1/Scl network subcircuit constitutes the first example of any network motif operating during the specification of mammalian stem cells where all the individual components have been identified and is already allowing us to develop novel hypotheses for experimental validation.