title: Genome-wide analysis of transcriptional regulators in human HSPCs reveals a densely interconnected network of coding and noncoding genes.
abstract: Genome-wide combinatorial binding patterns for key transcription factors (TFs) have not been reported for primary human hematopoietic stem and progenitor cells (HSPCs), and have constrained analysis of the global architecture of 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 catalog binding of TFs at coding genes and microRNA promoters, and report that combinatorial binding of all 7 TFs is favored and associated with differential expression of genes and microRNA in HSPCs. We also uncover a previously unrecognized association between FLI1 and RUNX1 pairing in HSPCs, we establish a correlation between the density of histone modifications that mark active enhancers and the number of overlapping TFs at a peak, we demonstrate bivalent histone marks at promoters of heptad target genes in CD34(+) cells that are poised for later expression, and we identify complex relationships between specific microRNAs and coding genes regulated by the heptad. Taken together, these data reveal the power of integrating multifactor sequencing of chromatin immunoprecipitates with coding and noncoding gene expression to identify regulatory circuits controlling cell identity.
authors: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia;
authors: Dominik
authors: D
authors: Beck
authors: Julie A I
authors: JA
authors: Thoms
authors: Dilmi
authors: D
authors: Perera
authors: Judith
authors: J
authors: Schütte
authors: Ashwin
authors: A
authors: Unnikrishnan
authors: Kathy
authors: K
authors: Knezevic
authors: Sarah J
authors: SJ
authors: Kinston
authors: Nicola K
authors: NK
authors: Wilson
authors: Tracey A
authors: TA
authors: O'Brien
authors: Berthold
authors: B
authors: Göttgens
authors: Jason W H
authors: JW
authors: Wong
authors: John E
authors: JE
authors: Pimanda
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D005434:Flow Cytometry; D055106:Genome-Wide Association Study; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D022661:RNA, Untranslated; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D022661:RNA, Untranslated; D014157:Transcription Factors