Dynamic analysis of gene expression and genome wide transcription factor binding during lineage-specification of multipotent progenitors [TC]

An expression time course experiment to investigate gene expression changes during differentiation of multipotential cells over two lineages using the model cell line FDCPmix differentiating towards erytroid and myeloid fates. We used the paradigmatic 'GATA-PU.1 axis’ to explore, at systems-level, dynamic relationships between transcription factor (TF) binding and global gene expression programs as multipotent cells differentiate. We combined global ChIPSeq of GATA1, GATA2 and PU.1 with expression profiling during differentiation to erythroid and neutrophil lineages. Our analysis reveals (i) differential complexity of sequence motifs bound by GATA1, GATA2 and PU.1; (ii) the scope and interplay of the GATA1 and GATA2 programs within, and during transitions between, different cell compartments, and the extent of their hard-wiring by DNA motifs; (iii) the potential to predict gene expression trajectories based on global associations between TF-binding data and target gene expression and (iv) how dynamic modeling of DNA-binding and gene expression data can be used to infer regulatory logic of TF circuitry. This 'rubric' exemplifies the utility of this cross-platform resource for deconvoluting the complexity of transcriptional programs controlling stem/progenitor cell fate in hematopoiesis. Multipotential FDCPmix cells were placed in two separate cytokine conditions and differentiated to erythroid and myeloid cells. Samples were taken at the time intervals indicated and hybridised to Agilent expression arrays. Each time point was done in triplicate.