title: PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells.
abstract: Inactivation of the Pancreatic and Duodenal Homeobox 1 (PDX1) gene causes pancreatic agenesis, which places PDX1 high atop the regulatory network controlling development of this indispensable organ. However, little is known about the identity of PDX1 transcriptional targets. We simulated pancreatic development by differentiating human embryonic stem cells (hESCs) into early pancreatic progenitors and subjected this cell population to PDX1 chromatin immunoprecipitation sequencing (ChIP-seq). We identified more than 350 genes bound by PDX1, whose expression was upregulated on day 17 of differentiation. This group included known PDX1 targets and many genes not previously linked to pancreatic development. ChIP-seq also revealed PDX1 occupancy at hepatic genes. We hypothesized that simultaneous PDX1-driven activation of pancreatic and repression of hepatic programs underlie early divergence between pancreas and liver. In HepG2 cells and differentiating hESCs, we found that PDX1 binds and suppresses expression of endogenous liver genes. These findings rebrand PDX1 as a context-dependent transcriptional repressor and activator within the same cell type.
authors.affiliation: Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore.
authors.forename: Adrian Kee Keong
authors.initials: AK
authors.lastname: Teo
authors.affiliation: Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Tsuneyoshi
authors.affiliation: Molecular Engineering Lab, A(∗)STAR, 61 Biopolis Drive, Proteos #03-13, Singapore 138673, Singapore.
authors.forename: Shawn
authors.initials: S
authors.lastname: Hoon
authors.affiliation: Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore.
authors.forename: Ee Kim
authors.initials: EK
authors.lastname: Tan
authors.affiliation: Genome Institute of Singapore, A(∗)STAR, 60 Biopolis Street, #02-01 Genome, Singapore 138672, Singapore.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
authors.affiliation: Department of Cell and Developmental Biology and Vanderbilt University Program in Developmental Biology, Vanderbilt University Medical Center, 3144 MRBIII, 465 21(st) Avenue South, Nashville, TN 37232, USA.
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.affiliation: Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore. Electronic address: ray.dunn@imb.a-star.edu.sg.
authors.forename: N Ray
authors.initials: NR
authors.lastname: Dunn
mesh_terms: D001665:Binding Sites; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D016000:Cluster Analysis; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics; D038081:Organogenesis / Q000235:genetics; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism*; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein
references.citation: Dev Biol. 2005 Apr 1;280(1):87-99
references.pmid: 15766750
references.citation: Nat Med. 2003 May;9(5):596-603
references.pmid: 12704384
references.citation: Mech Dev. 2005 Jun;122(6):835-47
references.pmid: 15939230
references.citation: Stem Cells. 2006 Aug;24(8):1923-30
references.pmid: 16675598
references.citation: Endocr J. 2006 Dec;53(6):789-95
references.pmid: 16983179
references.citation: Diabetologia. 2007 Jan;50(1):121-30
references.pmid: 17131142
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1865-70
references.pmid: 17267606
references.citation: Development. 2007 Jul;134(13):2521-31
references.pmid: 17522155
references.citation: Hepatology. 2007 Sep;46(3):898-905
references.pmid: 17705277
references.citation: Endocr Rev. 2007 Oct;28(6):685-705
references.pmid: 17881611
references.citation: J Biol Chem. 2007 Nov 2;282(44):32084-92
references.pmid: 17761679
references.citation: BMC Dev Biol. 2007;7:129
references.pmid: 18036209
references.citation: Dev Biol. 2008 Feb 15;314(2):406-17
references.pmid: 18155690
references.citation: J Cell Biochem. 2008 May 1;104(1):224-36
references.pmid: 17979180
references.citation: Genome Biol. 2008;9(6):R99
references.pmid: 18554416
references.citation: Nucleic Acids Res. 1996 Jun 15;24(12):2288-94
references.pmid: 8710498
references.citation: Genes Dev. 1996 Jul 1;10(13):1670-82
references.pmid: 8682297
references.citation: J Biol Chem. 2003 Aug 22;278(34):31950-7
references.pmid: 12775714
references.citation: Nat Genet. 1997 Jan;15(1):106-10
references.pmid: 8988180
references.citation: Nat Genet. 1997 Oct;17(2):138-9
references.pmid: 9326926
references.citation: Genes Dev. 1998 Jun 15;12(12):1763-8
references.pmid: 9637677
references.citation: Mol Cell Biol. 1998 Sep;18(9):5109-20
references.pmid: 9710595
references.citation: Development. 1998 Dec;125(24):4909-17
references.pmid: 9811575
references.citation: Biochem Biophys Res Commun. 2005 Jan 14;326(2):402-9
references.pmid: 15582592
references.citation: BMC Genomics. 2008;9:511
references.pmid: 18973680
references.citation: Stem Cells. 2009 Feb;27(2):341-51
references.pmid: 19056911
references.citation: Cell. 2009 Nov 13;139(4):791-801
references.pmid: 19914171
references.citation: Dev Dyn. 2010 Mar;239(3):980-6
references.pmid: 20108349
references.citation: Methods Mol Biol. 2010;636:251-83
references.pmid: 20336528
references.citation: Genome Res. 2010 Aug;20(8):1037-51
references.pmid: 20551221
references.citation: Development. 2010 Dec;137(24):4295-305
references.pmid: 21098570
references.citation: Dev Dyn. 2011 Mar;240(3):530-65
references.pmid: 21337462
references.citation: Trends Endocrinol Metab. 2011 Sep;22(9):364-73
references.pmid: 21719305
references.citation: Diabetologia. 2012 Mar;55(3):707-18
references.pmid: 22167125
references.citation: Mol Endocrinol. 2012 Mar;26(3):521-33
references.pmid: 22322596
references.citation: Mech Dev. 2012 Jan-Feb;128(11-12):597-609
references.pmid: 22230751
references.citation: PLoS One. 2012;7(7):e40707
references.pmid: 22815796
references.citation: Stem Cells. 2012 Apr;30(4):631-42
references.pmid: 22893457
references.citation: Development. 2012 Sep;139(18):3363-72
references.pmid: 22874919
references.citation: Genes Dev. 2012 Nov 15;26(22):2471-6
references.pmid: 23154981
references.citation: Nat Rev Cancer. 2013 Jul;13(7):482-95
references.pmid: 23792361
references.citation: Diabetes. 2013 Oct;62(10):3514-22
references.pmid: 23630303
references.citation: Annu Rev Cell Dev Biol. 2013;29:81-105
references.pmid: 23909279
references.citation: Cell Metab. 2014 Feb 4;19(2):259-71
references.pmid: 24506867
references.citation: Mol Cell Biol. 1999 Dec;19(12):8219-25
references.pmid: 10567547
references.citation: Genesis. 2000 Feb;26(2):143-4
references.pmid: 10686611
references.citation: Nat Med. 2000 May;6(5):568-72
references.pmid: 10802714
references.citation: Mol Cell Biol. 2000 Oct;20(20):7583-90
references.pmid: 11003654
references.citation: Development. 2000 Nov;127(22):4915-23
references.pmid: 11044405
references.citation: Mol Cell Biol. 2000 Nov;20(22):8623-33
references.pmid: 11046157
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1065-70
references.pmid: 11158595
references.citation: Development. 2001 Mar;128(6):871-81
references.pmid: 11222142
references.citation: Development. 2004 Jan;131(1):165-79
references.pmid: 14660441
references.citation: EMBO J. 1993 Nov;12(11):4251-9
references.pmid: 7901001
references.citation: Nature. 1994 Oct 13;371(6498):606-9
references.pmid: 7935793
references.citation: Development. 1995 Jan;121(1):11-8
references.pmid: 7867492
references.citation: Mol Cell Biol. 1995 Dec;15(12):7091-7
references.pmid: 8524276
references.citation: Development. 1996 Mar;122(3):983-95
references.pmid: 8631275
references.citation: Development. 1996 May;122(5):1409-16
references.pmid: 8625829
references.citation: J Biol Chem. 2001 May 25;276(21):17985-93
references.pmid: 11279116
references.citation: J Biol Chem. 2002 Apr 12;277(15):13286-93
references.pmid: 11825903
references.citation: Development. 2002 May;129(10):2447-57
references.pmid: 11973276
references.citation: Curr Biol. 2003 Jan 21;13(2):105-15
references.pmid: 12546783
references.citation: Diabetes. 2005 Apr;54(4):1009-22
references.pmid: 15793239