Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators.
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.
Wilson
Nicola K
NK
University of Cambridge Department of Haematology, Cambridge Institute for Medical Research, Hills Road, Cambridge, CB2 0XY, UK.
Foster
Samuel D
SD
Wang
Xiaonan
X
Knezevic
Kathy
K
Schütte
Judith
J
Kaimakis
Polynikis
P
Chilarska
Paulina M
PM
Kinston
Sarah
S
Ouwehand
Willem H
WH
Dzierzak
Elaine
E
Pimanda
John E
JE
de Bruijn
Marella F T R
MF
Göttgens
Berthold
B
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*
D014157:Transcription Factors