Gene regulatory network dynamics of normal and perturbed haematopoiesis.

We will leverage our recent work identifying cellular pathways of blood cell differentiation to understand the transcriptional mechanisms by how blood cell types are specified, and how this process is regulated by environmental and oncogenic perturbation: 1. We will identify and systematically validate gene regulatory networks that control the successive blood lineage bifurcations that generate lineage-restricted progenitor cells from multi-potent blood stem cells, and in particular identify the regulatory interactions between the transcription factors (TFs) within each GRN. 2. We will analyse how perturbations that increase specific lineage outputs (emergency erythropoiesis, ageing, infection, mutations) affect successive GRNs specifying the affected lineage(s), and use modelling to understand how GRNs interact and/or are coordinated. 3. We will use this knowledge to predict how selective perturbation of regulatory elements regulate baseline and perturbed GRN function, and generate modified GRNs with the potential to counteract age-related, inflammatory and oncogenic perturbations in order to validate these predictions in vivo and refine the computational model of blood specification. Overall, this will generate a quantum leap in our understanding of blood cell specification, replacing the current state-of-the-art based on antagonism between TF pairs and inferred GRNs with validated GRNs and computational modelling with predictive capability.