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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE22178 | GEO | 2010/10/07

SECONDARY ACCESSION(S): PRJNA127555

REPOSITORIES: GEO

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

Project description: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. 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).

2010-10-07 | E-GEOD-22178 | biostudies-arrayexpress

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Genome-wide Analysis of Transcriptional Regulators in Human Blood Stem/Progenitor Cells reveals a densely interconnected network of coding and non-coding genes.

Project description:Combinatorial transcription factor (TF) interactions regulate hematopoietic stem cell formation, maintenance and differentiation, and are increasingly recognised as drivers of stem cell signatures in cancer. However, genome-wide combinatorial binding patterns for key regulators do not exist in 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 new high-resolution genome-wide binding maps of seven 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 favoured 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, this study demonstrates that a heptad of TFs forms a dense auto-regulatory core in human HSPCs with binding of all seven TFs at tissue specific regulatory elements of heptad genes and collectively regulates miRNAs that in turn target components of the heptad and genes regulated by the heptad. Examination of cominatorial binding by 7 transcription factors, 1 IgG control along with mRNA and small RNA sequencing in human CD34+ cells

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