Combinatorial Transcriptional Control in Blood Stem/Progenitor Cells: Genome-wide Analysis of 10 major Transcriptional Regulators. Mus musculus

Combinatorial transcription factor (TF) interactions control cellular phenotypes and therefore underpin stem cell formation, maintenance and differentiation. Here we report the genome-wide binding patterns and combinatorial interactions for 10 key regulators of blood stem/progenitor cells (Scl/Tal1, Lyl1, Lmo2, Gata2, Runx1, Meis1, Pu.1, Erg, Fli-1, Gfi1b) thus providing the most comprehensive TF dataset for any adult stem/progenitor cell type to date. Genome-wide computational analysis of complex binding patterns followed by functional validation revealed the following: First, a previously unrecognized combinatorial interaction between a heptad of TFs (Scl, Lyl1, Lmo2, Gata2, Runx1, Erg, Fli-1). Second, we implicate direct protein-protein interactions between four key regulators (Runx1, Gata2, Scl, Erg) in stabilising complex binding to DNA. Third, Runx1+/-::Gata2+/- compound heterozygous mice are not viable with severe haematopoietic defects at midgestation. Taken together, this study demonstrates the power of genome-wide analysis in generating novel functional insights into the transcriptional control of stem and progenitor cells. Overall design: 10 Samples (9 Transcription Factors and 1 Histone Modification) and 1 Control (IgG). All from the same cell line, a haematopoietic progenitor cell line (HPC-7).