XB-ART-45701
Cell Rep
February 23, 2012;
1
(2):
99-109.
Transcriptional activation by Oct4 is sufficient for the maintenance and induction of pluripotency.
Hammachi F
,
Morrison GM
,
Sharov AA
,
Livigni A
,
Narayan S
,
Papapetrou EP
,
O'Malley J
,
Kaji K
,
Ko MS
,
Ptashne M
,
Brickman JM
.
Abstract
Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing the coding sequence of Oct4 or Xlpou91 (the Xenopus homolog of Oct4) fused to activating regions, but not those fused to repressing regions, behave as Oct4, suppressing differentiation and promoting maintenance of undifferentiated phenotypes in vivo and in vitro. An Oct4 activation domain fusion supported embryonic stem cell self-renewal in vitro at lower concentrations than that required for Oct4 while alleviating the ordinary requirement for the cytokine LIF. At still lower levels of the fusion, LIF dependence was restored. We conclude that the necessary and sufficient function of Oct4 in promoting pluripotency is to activate specific target genes.
PubMed ID: 22832160
PMC ID: PMC3778438
Article link: Cell Rep
Grant support: [+]
BB/C506605 Biotechnology and Biological Sciences Research Council , G0701428 Medical Research Council , Z01AG AG000656 NIA NIH HHS , Z01AG000662 NIA NIH HHS , 079249 Wellcome Trust , G0701429 Medical Research Council , Intramural NIH HHS, Z01 AG000662 NIA NIH HHS , Z01 AG000656 NIA NIH HHS , MRC_G0701429 Medical Research Council , WT079249 Wellcome Trust , Z01 AG000662 Intramural NIH HHS, Z01 AG000656 Intramural NIH HHS
Species referenced: Xenopus laevis
Genes referenced: bmp4 cdh1 cdx2 fgf4 gsc klf4 lif mixer myc npat pou5f3.1 rexo1 rpl7 sox17a sox2 tbp tra
Article Images: [+] show captions
References [+] :
Ang,
Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network.
2011, Pubmed
Ang,
Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network.
2011,
Pubmed
Baron, Tetracycline-controlled transcription in eukaryotes: novel transactivators with graded transactivation potential. 1997, Pubmed
Bilodeau, SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. 2009, Pubmed
Boyer, Core transcriptional regulatory circuitry in human embryonic stem cells. 2005, Pubmed
Boyer, Polycomb complexes repress developmental regulators in murine embryonic stem cells. 2006, Pubmed
Brickman, Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. 2001, Pubmed
Brickman, Hex is a transcriptional repressor that contributes to anterior identity and suppresses Spemann organiser function. 2000, Pubmed , Xenbase
Cao, Xenopus POU factors of subclass V inhibit activin/nodal signaling during gastrulation. 2006, Pubmed , Xenbase
Carter, Transcript copy number estimation using a mouse whole-genome oligonucleotide microarray. 2005, Pubmed
Chamberlain, Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. 2008, Pubmed
Chambers, Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. 2003, Pubmed
Chen, Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. 2008, Pubmed
Chew, Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. 2005, Pubmed
Evans, Establishment in culture of pluripotential cells from mouse embryos. 1981, Pubmed
Gill, Negative effect of the transcriptional activator GAL4. 1988, Pubmed
Hall, Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. 2009, Pubmed
Hay, Oct-4 knockdown induces similar patterns of endoderm and trophoblast differentiation markers in human and mouse embryonic stem cells. 2004, Pubmed
Hirai, Radical acceleration of nuclear reprogramming by chromatin remodeling with the transactivation domain of MyoD. 2011, Pubmed
Hobert, Regulatory logic of neuronal diversity: terminal selector genes and selector motifs. 2008, Pubmed
Kaji, Virus-free induction of pluripotency and subsequent excision of reprogramming factors. 2009, Pubmed
Kim, An extended transcriptional network for pluripotency of embryonic stem cells. 2008, Pubmed
Kim, Oct4-induced pluripotency in adult neural stem cells. 2009, Pubmed
Lavial, The Oct4 homologue PouV and Nanog regulate pluripotency in chicken embryonic stem cells. 2007, Pubmed , Xenbase
Livigni, Differentiation of embryonic stem cells into anterior definitive endoderm. 2009, Pubmed
Loh, The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. 2006, Pubmed
Loh, A precarious balance: pluripotency factors as lineage specifiers. 2011, Pubmed
Lunde, Zebrafish pou5f1/pou2, homolog of mammalian Oct4, functions in the endoderm specification cascade. 2004, Pubmed
Martin, Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. 1982, Pubmed
Morrison, Conserved roles for Oct4 homologues in maintaining multipotency during early vertebrate development. 2006, Pubmed , Xenbase
Navarro, Molecular coupling of Xist regulation and pluripotency. 2008, Pubmed
Nichols, Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. 1998, Pubmed
Niwa, Efficient selection for high-expression transfectants with a novel eukaryotic vector. 1992, Pubmed
Niwa, Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. 2000, Pubmed
Niwa, Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. 1998, Pubmed
Niwa, Phenotypic complementation establishes requirements for specific POU domain and generic transactivation function of Oct-3/4 in embryonic stem cells. 2002, Pubmed
Ohashi, Modulating the potency of an activator in a yeast in vitro transcription system. 1994, Pubmed
Palmieri, Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. 1994, Pubmed
Pan, Stem cell pluripotency and transcription factor Oct4. 2003, Pubmed
Papapetrou, Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation. 2009, Pubmed
Pardo, An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. 2010, Pubmed
Pasini, JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. 2010, Pubmed
Ptashne, Binding reactions: epigenetic switches, signal transduction and cancer. 2009, Pubmed
Reim, The POU domain protein spg (pou2/Oct4) is essential for endoderm formation in cooperation with the HMG domain protein casanova. 2004, Pubmed
Schoeftner, Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. 2006, Pubmed
Sharov, A web-based tool for principal component and significance analysis of microarray data. 2005, Pubmed
Sharov, Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data. 2008, Pubmed
Smith, Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. 1989, Pubmed
Struhl, Fundamentally different logic of gene regulation in eukaryotes and prokaryotes. 1999, Pubmed
Takahashi, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. 2006, Pubmed
Wang, Reprogramming of mouse and human somatic cells by high-performance engineered factors. 2011, Pubmed
Wang, Nucleosomes and the accessibility problem. 2011, Pubmed
Williams, Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. 1989, Pubmed
Yeap, ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. 2009, Pubmed
Ying, BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. 2003, Pubmed
Ying, The ground state of embryonic stem cell self-renewal. 2008, Pubmed
Yuan, Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. 2009, Pubmed
Zamparini, Hex acts with beta-catenin to regulate anteroposterior patterning via a Groucho-related co-repressor and Nodal. 2006, Pubmed , Xenbase
Baron, Tetracycline-controlled transcription in eukaryotes: novel transactivators with graded transactivation potential. 1997, Pubmed
Bilodeau, SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. 2009, Pubmed
Boyer, Core transcriptional regulatory circuitry in human embryonic stem cells. 2005, Pubmed
Boyer, Polycomb complexes repress developmental regulators in murine embryonic stem cells. 2006, Pubmed
Brickman, Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. 2001, Pubmed
Brickman, Hex is a transcriptional repressor that contributes to anterior identity and suppresses Spemann organiser function. 2000, Pubmed , Xenbase
Cao, Xenopus POU factors of subclass V inhibit activin/nodal signaling during gastrulation. 2006, Pubmed , Xenbase
Carter, Transcript copy number estimation using a mouse whole-genome oligonucleotide microarray. 2005, Pubmed
Chamberlain, Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. 2008, Pubmed
Chambers, Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. 2003, Pubmed
Chen, Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. 2008, Pubmed
Chew, Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. 2005, Pubmed
Evans, Establishment in culture of pluripotential cells from mouse embryos. 1981, Pubmed
Gill, Negative effect of the transcriptional activator GAL4. 1988, Pubmed
Hall, Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. 2009, Pubmed
Hay, Oct-4 knockdown induces similar patterns of endoderm and trophoblast differentiation markers in human and mouse embryonic stem cells. 2004, Pubmed
Hirai, Radical acceleration of nuclear reprogramming by chromatin remodeling with the transactivation domain of MyoD. 2011, Pubmed
Hobert, Regulatory logic of neuronal diversity: terminal selector genes and selector motifs. 2008, Pubmed
Kaji, Virus-free induction of pluripotency and subsequent excision of reprogramming factors. 2009, Pubmed
Kim, An extended transcriptional network for pluripotency of embryonic stem cells. 2008, Pubmed
Kim, Oct4-induced pluripotency in adult neural stem cells. 2009, Pubmed
Lavial, The Oct4 homologue PouV and Nanog regulate pluripotency in chicken embryonic stem cells. 2007, Pubmed , Xenbase
Livigni, Differentiation of embryonic stem cells into anterior definitive endoderm. 2009, Pubmed
Loh, The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. 2006, Pubmed
Loh, A precarious balance: pluripotency factors as lineage specifiers. 2011, Pubmed
Lunde, Zebrafish pou5f1/pou2, homolog of mammalian Oct4, functions in the endoderm specification cascade. 2004, Pubmed
Martin, Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. 1982, Pubmed
Morrison, Conserved roles for Oct4 homologues in maintaining multipotency during early vertebrate development. 2006, Pubmed , Xenbase
Navarro, Molecular coupling of Xist regulation and pluripotency. 2008, Pubmed
Nichols, Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. 1998, Pubmed
Niwa, Efficient selection for high-expression transfectants with a novel eukaryotic vector. 1992, Pubmed
Niwa, Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. 2000, Pubmed
Niwa, Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. 1998, Pubmed
Niwa, Phenotypic complementation establishes requirements for specific POU domain and generic transactivation function of Oct-3/4 in embryonic stem cells. 2002, Pubmed
Ohashi, Modulating the potency of an activator in a yeast in vitro transcription system. 1994, Pubmed
Palmieri, Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. 1994, Pubmed
Pan, Stem cell pluripotency and transcription factor Oct4. 2003, Pubmed
Papapetrou, Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation. 2009, Pubmed
Pardo, An expanded Oct4 interaction network: implications for stem cell biology, development, and disease. 2010, Pubmed
Pasini, JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. 2010, Pubmed
Ptashne, Binding reactions: epigenetic switches, signal transduction and cancer. 2009, Pubmed
Reim, The POU domain protein spg (pou2/Oct4) is essential for endoderm formation in cooperation with the HMG domain protein casanova. 2004, Pubmed
Schoeftner, Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. 2006, Pubmed
Sharov, A web-based tool for principal component and significance analysis of microarray data. 2005, Pubmed
Sharov, Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data. 2008, Pubmed
Smith, Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. 1989, Pubmed
Struhl, Fundamentally different logic of gene regulation in eukaryotes and prokaryotes. 1999, Pubmed
Takahashi, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. 2006, Pubmed
Wang, Reprogramming of mouse and human somatic cells by high-performance engineered factors. 2011, Pubmed
Wang, Nucleosomes and the accessibility problem. 2011, Pubmed
Williams, Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. 1989, Pubmed
Yeap, ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. 2009, Pubmed
Ying, BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. 2003, Pubmed
Ying, The ground state of embryonic stem cell self-renewal. 2008, Pubmed
Yuan, Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. 2009, Pubmed
Zamparini, Hex acts with beta-catenin to regulate anteroposterior patterning via a Groucho-related co-repressor and Nodal. 2006, Pubmed , Xenbase