Reactome: A Curated Pathway Database

Transcriptional regulation of pluripotent stem cells (R-HSA-452723)

Species Homo sapiens


Pluripotent stem cells are undifferentiated cells posessing an abbreviated cell cycle (reviewed in Stein et al. 2012), a characteristic profile of gene expression (Rao et al. 2004, Kim et al. 2006, Player et al. 2006, Wang et al 2006 using mouse, International Stem Cell Initiative 2007, Assou et al. 2007, Assou et al. 2009, Ding et al. 2012 using mouse), and the ability to self-renew and generate all cell types of the body except extraembryonic lineages (Marti et al. 2013, reviewed in Romeo et al. 2012). They are a major cell type in the inner cell mass of the early embryo in vivo, and cells with the same properties, induced pluripotent stem cells, can be generated in vitro from differentiated adult cells by overexpression of a set of transcription factor genes (Takahashi and Yamanaka 2006, Takahashi et al. 2007, Yu et al. 2007, Jaenisch and Young 2008, Stein et al. 2012, reviewed in Dejosez and Zwaka 2012).
Pluripotency is maintained by a self-reinforcing loop of transcription factors (Boyer et al. 2005, Rao et al. 2006, Matoba et al. 2006, Player et al. 2006, Babaie et al. 2007, Sun et al. 2008, Assou et al. 2009, reviewed in Kashyap et al. 2009, reviewed in Dejosez and Zwaka 2012). In vivo, initiation of pluripotency may depend on maternal factors transmitted through the oocyte (Assou et al. 2009) and on DNA demethylation in the zygote (recently reviewed in Seisenberger et al. 2013) and hypoxia experienced by the blastocyst in the reproductive tract before implantation (Forristal et al. 2010, reviewed in Mohyeldin et al. 2010). In vitro, induced pluripotency may initiate with demethylation and activation of the promoters of POU5F1 (OCT4) and NANOG (Bhutani et al. 2010). Hypoxia also significantly enhances conversion to pluripotent stem cells (Yoshida et al. 2009). POU5F1 and NANOG, together with SOX2, encode central factors in pluripotency and activate their own transcription (Boyer et al 2005, Babaie et al. 2007, Yu et al. 2007, Takahashi et al. 2007). The autoactivation loop maintains expression of POU5F1, NANOG, and SOX2 at high levels in stem cells and, in turn, complexes containing various combinations of these factors (Remenyi et al. 2003, Lam et al. 2012) activate the expression of a group of genes whose products are associated with rapid cell proliferation and repress the expression of a group of genes whose products are associated with cell differentiation (Boyer et al. 2005, Matoba et al. 2006, Babaie et al. 2007, Chavez et al. 2009, Forristal et al. 2010, Guenther 2011).
Comparisons between human and mouse embryonic stem cells must be made with caution and for this reason inferences from mouse have been used sparingly in this module. Human ESCs more closely resemble mouse epiblast stem cells in having inactivated X chromosomes, flattened morphology, and intolerance to passaging as single cells (Hanna et al. 2010). Molecularly, human ESCs differ from mouse ESCs in being maintained by FGF and Activin/Nodal/TGFbeta signaling rather than by LIF and canonical Wnt signaling (Greber et al. 2010, reviewed in Katoh 2011). In human ESCs POU5F1 binds and directly activates the FGF2 gene, however Pou5f1 does not activate Fgf2 in mouse ESCs (reviewed in De Los Angeles et al. 2012). Differences in expression patterns of KLF2, KLF4, KLF5, ESRRB, FOXD3, SOCS3, LIN28, NODAL were observed between human and mouse ESCs (Cai et al. 2010) as were differences in expression of EOMES, ARNT and several other genes (Ginis et al.2004).

Locations in the PathwayBrowser
Additional Information
Compartment cytosol , nucleoplasm
GO Biological Process somatic stem cell maintenance (0035019)
Cross References
Database Identifier
BioModels Database BIOMD0000000209, BIOMD0000000210
Literature References
pubMedId Title Journal Year
19128516 A gene expression signature shared by human mature oocytes and embryonic stem cells BMC Genomics 2009
17204602 A meta-analysis of human embryonic stem cells transcriptome integrated into a web-based expression atlas Stem Cells 2007
17068183 Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells Stem Cells 2007
16978057 Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan Stem Cells Dev 2006
17572666 Characterization of human embryonic stem cell lines by the International Stem Cell Initiative Nat Biotechnol 2007
15493035 Comparative transcriptional profiling of two human embryonic stem cell lines Biotechnol Bioeng 2004
16846370 Comparisons between transcriptional regulation and RNA expression in human embryonic stem cell lines Stem Cells Dev 2006
16153702 Core transcriptional regulatory circuitry in human embryonic stem cells Cell 2005
15110706 Differences between human and mouse embryonic stem cells Dev Biol 2004
17183653 Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profiling PLoS One 2006
18923680 Evolutionarily conserved transcriptional co-expression guiding embryonic stem cell differentiation PLoS One 2008
19604364 In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach BMC Genomics 2009
18029452 Induced pluripotent stem cell lines derived from human somatic cells Science 2007
18035408 Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 2007
16819296 Profiling of differentially expressed genes in human stem cells by cDNA microarray Mol Cells 2006
19755485 Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions Reproduction 2010
20027182 Reprogramming towards pluripotency requires AID-dependent DNA demethylation Nature 2009
22463982 Accessing na´ve human pluripotency Curr. Opin. Genet. Dev. 2012
21044011 Network of WNT and other regulatory signaling cascades in pluripotent stem cells and cancer stem cells Curr Pharm Biotechnol 2011
12923055 Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers Genes Dev 2003
22909387 DNA-dependent Oct4-Sox2 interaction and diffusion properties characteristic of the pluripotent cell state revealed by fluorescence spectroscopy Biochem. J. 2012
22443931 Pluripotency and nuclear reprogramming Annu. Rev. Biochem. 2012
23306458 Characterization of pluripotent stem cells Nat Protoc 2013
22394165 The architectural organization of human stem cell cycle regulatory machinery Curr. Pharm. Des. 2012
22122341 Transcriptional control of embryonic and induced pluripotent stem cells Epigenomics 2011
20207225 Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells Cell Stem Cell 2010
23248145 Embryonic stem cells and inducible pluripotent stem cells: two faces of the same coin? Aging (Albany NY) 2012
19480567 Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs Stem Cells Dev. 2009
23166394 Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2013
17093407 A protein interaction network for pluripotency of embryonic stem cells Nature 2006
22083510 Oct4 links multiple epigenetic pathways to the pluripotency network Cell Res. 2012
20300647 Modeling co-expression across species for complex traits: insights to the difference of human and mouse embryonic stem cells PLoS Comput. Biol. 2010