Pluripotency factors regulate definitive endoderm specification through eomesodermin.
Understanding the molecular mechanisms controlling early cell fate decisions in mammals is a major objective toward the development of robust methods for the differentiation of human pluripotent stem cells into clinically relevant cell types. Here, we used human embryonic stem cells and mouse epiblast stem cells to study specification of definitive endoderm in vitro. Using a combination of whole-genome expression and chromatin immunoprecipitation (ChIP) deep sequencing (ChIP-seq) analyses, we established an hierarchy of transcription factors regulating endoderm specification. Importantly, the pluripotency factors NANOG, OCT4, and SOX2 have an essential function in this network by actively directing differentiation. Indeed, these transcription factors control the expression of EOMESODERMIN (EOMES), which marks the onset of endoderm specification. In turn, EOMES interacts with SMAD2/3 to initiate the transcriptional network governing endoderm formation. Together, these results provide for the first time a comprehensive molecular model connecting the transition from pluripotency to endoderm specification during mammalian development.
Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK.
Adrian Kee Keong
AK
Teo
Sebastian J
SJ
Arnold
Matthew W B
MW
Trotter
Stephanie
S
Brown
Lay Teng
LT
Ang
Zhenzhi
Z
Chng
Elizabeth J
EJ
Robertson
N Ray
NR
Dunn
Ludovic
L
Vallier
D028341:Activins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D000071317:Nanog Homeobox Protein; D055457:Nodal Protein / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; C491199:EOMES protein, human; C491198:Eomes protein, mouse; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D055457:Nodal Protein; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors; D020825:T-Box Domain Proteins; D028341:Activins
Nature. 2007 Jul 12;448(7150):191-5
17597762
Nature. 2009 Jul 2;460(7251):118-22
19571885
Science. 1998 Nov 6;282(5391):1145-7
9804556
Dev Cell. 2009 Apr;16(4):517-27
19386261
Curr Biol. 2004 Jan 6;14(1):48-55
14711414
Nat Biotechnol. 2005 Dec;23(12):1534-41
16258519
Development. 2006 Jul;133(13):2497-505
16728477
Nat Genet. 2006 Apr;38(4):431-40
16518401
Development. 1995 Sep;121(9):3005-12
7555726
Cell Stem Cell. 2008 Nov 6;3(5):543-54
18804426
Mol Pharmacol. 2002 Jul;62(1):65-74
12065756
Stem Cells. 2007 Jul;25(7):1664-74
17446562
Cell Stem Cell. 2009 Dec 4;5(6):597-609
19951688
Cell Stem Cell. 2010 Mar 5;6(3):215-26
20207225
Development. 2002 May;129(10):2367-79
11973269
Stem Cells. 2009 Nov;27(11):2655-66
19688839
Development. 2002 Aug;129(15):3597-608
12117810
Nat Rev Mol Cell Biol. 2009 Feb;10(2):91-103
19129791
Cell. 2005 Sep 23;122(6):947-56
16153702
Mol Cell Biol. 2005 Jul;25(14):6031-46
15988017
J Cell Sci. 2005 Oct 1;118(Pt 19):4495-509
16179608
Development. 2001 Jan;128(2):167-80
11124113
Nature. 2000 Mar 2;404(6773):95-9
10716450
Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
16493418
Hepatology. 2010 May;51(5):1754-65
20301097
Nature. 2007 Jul 12;448(7150):196-9
17597760
Nature. 2007 Sep 13;449(7159):183-8
17728715
Cell Stem Cell. 2008 Aug 7;3(2):196-206
18682241
Nat Biotechnol. 2000 Apr;18(4):399-404
10748519
Dev Dyn. 2004 May;230(1):187-98
15108323
Dev Dyn. 2008 Feb;237(2):464-75
18213575
Development. 2003 Dec;130(25):6283-94
14623818
Development. 1998 Aug;125(16):3015-25
9671576
Cell Stem Cell. 2010 Jan 8;6(1):59-70
20074535
Genes Dev. 2003 Jul 1;17(13):1646-62
12842913
Dev Biol. 2004 Jun 1;270(1):47-63
15136140
PLoS One. 2009 Jun 30;4(6):e6082
19564924
Development. 2001 Oct;128(19):3749-58
11585801
Dev Biol. 2004 Nov 15;275(2):403-21
15501227
Nat Genet. 2000 Apr;24(4):372-6
10742100
Genes Dev. 2003 Jan 1;17(1):126-40
12514105
Development. 2008 Feb;135(3):501-11
18171685
J Biol Chem. 2009 Jan 23;284(4):2397-408
19036723
Development. 2009 Apr;136(8):1339-49
19279133