Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors.
To examine transcription factor (TF) network(s), we created mouse ESC lines, in each of which 1 of 50 TFs tagged with a FLAG moiety is inserted into a ubiquitously controllable tetracycline-repressible locus. Of the 50 TFs, Cdx2 provoked the most extensive transcriptome perturbation in ESCs, followed by Esx1, Sox9, Tcf3, Klf4, and Gata3. ChIP-Seq revealed that CDX2 binds to promoters of upregulated target genes. By contrast, genes downregulated by CDX2 did not show CDX2 binding but were enriched with binding sites for POU5F1, SOX2, and NANOG. Genes with binding sites for these core TFs were also downregulated by the induction of at least 15 other TFs, suggesting a common initial step for ESC differentiation mediated by interference with the binding of core TFs to their target genes. These ESC lines provide a fundamental resource to study biological networks in ESCs and mice.
National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Akira
A
Nishiyama
Li
L
Xin
Alexei A
AA
Sharov
Marshall
M
Thomas
Gregory
G
Mowrer
Emily
E
Meyers
Yulan
Y
Piao
Samir
S
Mehta
Sarah
S
Yee
Yuhki
Y
Nakatake
Carole
C
Stagg
Lioudmila
L
Sharova
Lina S
LS
Correa-Cerro
Uwem
U
Bassey
Hien
H
Hoang
Eugene
E
Kim
Richard
R
Tapnio
Yong
Y
Qian
Dawood
D
Dudekula
Michal
M
Zalzman
Manxiang
M
Li
Geppino
G
Falco
Hsih-Te
HT
Yang
Sung-Lim
SL
Lee
Manuela
M
Monti
Ilaria
I
Stanghellini
Md Nurul
MN
Islam
Ramaiah
R
Nagaraja
Ilya
I
Goldberg
Weidong
W
Wang
Dan L
DL
Longo
David
D
Schlessinger
Minoru S H
MS
Ko
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D047468:Immunoprecipitation; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D000071616:CDX2 Transcription Factor; D050990:GATA3 Transcription Factor; D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D055758:SOX9 Transcription Factor; D014157:Transcription Factors; C487514:Cdx2 protein, mouse; C107475:Esx1 protein, mouse; C000715468:Klf4 protein, mouse; C527933:Sox9 protein, mouse; C075668:Tcf3 protein, mouse