title: Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten 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 ten key regulators of blood stem/progenitor cells (SCL/TAL1, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1, and GFI1B), thus providing the most comprehensive TF data set 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, and FLI-1). Second, we implicate direct protein-protein interactions between four key regulators (RUNX1, GATA2, SCL, and ERG) in stabilizing complex binding to DNA. Third, Runx1(+/-)::Gata2(+/-) compound heterozygous mice are not viable with severe hematopoietic 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.
authors.affiliation: University of Cambridge Department of Haematology, Cambridge Institute for Medical Research, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Wilson
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Foster
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Kathy
authors.initials: K
authors.lastname: Knezevic
authors.forename: Judith
authors.initials: J
authors.lastname: Schütte
authors.forename: Polynikis
authors.initials: P
authors.lastname: Kaimakis
authors.forename: Paulina M
authors.initials: PM
authors.lastname: Chilarska
authors.forename: Sarah
authors.initials: S
authors.lastname: Kinston
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Elaine
authors.initials: E
authors.lastname: Dzierzak
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.forename: Marella F T R
authors.initials: MF
authors.lastname: de Bruijn
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics*; D016678:Genome; D055106:Genome-Wide Association Study; D051379:Mice; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D014157:Transcription Factors