Abstract| Volume 41, ISSUE 8, SUPPLEMENT , S17, August 2013

Genome-wide analysis of transcriptional regulators in human hscs reveals a densely interconnected network of coding and non-coding genes

      Combinatorial transcription factor (TF) interactions regulate hematopoietic stem cell (HSC) formation, maintenance and differentiation, and are recognized as drivers of stem cell signatures in cancer. However, genome-wide combinatorial binding patterns for key regulators have not been reported for primary human hematopoietic stem/progenitor cells (HSPCs) and have constrained analysis of the global architecture of the molecular circuits controlling these cells. Here we provide high-resolution genome-wide binding maps for a heptad of key TFs (FLI1, ERG, GATA2, RUNX1, SCL, LYL1 and LMO2) in human CD34+ HSPCs together with quantitative RNA and microRNA expression profiles. We catalogue binding of TFs at coding genes and microRNA promoters and report that combinatorial binding of all seven TFs is favored and is associated with differential expression of genes and microRNA in HSPCs. We also uncover a hitherto unrecognized association between FLI1 and RUNX1 pairing in HSPCs, establish a correlation between the density of histone modifications, which mark active enhancers and the number of overlapping TFs at a peak and identify complex relationships between specific miRNAs and coding genes regulated by the heptad. Taken together, these data reveal the power of integrating multifactor ChIP-seq with coding and non-coding gene expression to identify regulatory circuits controlling cell identity.