The transcriptional foundation of pluripotency

Chambers, Ian; Tomlinson, Simon R.

doi:10.1242/dev.024398

Cited by 403 publications

(343 citation statements)

References 83 publications

(153 reference statements)

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“…Many studies focused on the regulation of pluripotency identified genes and factors important for the maintenance of the pluripotent state. Among them are the transcription factor encoding genes Oct3/4 (Pou5f1), Sox2, Sall4, and Nanog (Chambers and Tomlinson, 2009). Oct3/4 is normally expressed by all cells in early cleaving mouse embryos, and after segregation of the trophectoderm, its transcripts become restricted to the pluripotent, embryo-forming, inner-cell mass cells (ICM).…”

Section: Introductionmentioning

confidence: 99%

Negative autoregulation of Oct3/4 through Cdx1 promotes the onset of gastrulation

et al. 2011

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Gastrulation marks the onset of germ layer formation from undifferentiated precursor cells maintained by a network including the Pou5f1 gene, Oct3/4. Negative regulation of the undifferentiated state is a prerequisite for germ layer formation and subsequent development. A novel cross-regulatory network was characterized including the Pou5f1 and Cdx1 genes as part of the signals controlling the onset of gastrulation. Of particular interest was the observation that, preceding gastrulation, the Xenopus Oct3/4 factors, Oct60, Oct25, and Oct91, positively regulate Cdx1 expression through FGF signaling, and during gastrulation the Oct3/4 factors become repressors of Cdx1. Cdx1 negatively regulates the Pou5f1 genes during gastrulation, thus contributing to the repression of the network maintaining the undifferentiated state and promoting the onset of gastrulation. These regulatory interactions suggest that Oct3/4 initiates its own negative autoregulation through Cdx1 up-regulation to begin the repression of pluripotency in preparation for the onset of gastrulation and germ layer differentiation. Developmental Dynamics 240:796-807,

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Section: Introductionmentioning

confidence: 99%

Negative autoregulation of Oct3/4 through Cdx1 promotes the onset of gastrulation

et al. 2011

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“…NANOG exerts its role in pluripotency in tight cooperation with two other pluripotency transcription factors, OCT4 (also known as POU5F1) and SOX2. Together, these three factors form a core transcriptional regulatory network essential for the acquisition and maintenance of ESC identity [7][8][9][10][11][12] . During mouse embryogenesis, these factors are highly expressed in the inner cell mass and their deletion causes early embryonic lethality 3,13,14 .…”

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confidence: 99%

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

et al. 2014

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NANOG is a pluripotency transcription factor in embryonic stem cells; however, its role in adult tissues remains largely unexplored. Here we show that mouse NANOG is selectively expressed in stratified epithelia, most notably in the oesophagus where the Nanog promoter is hypomethylated. Interestingly, inducible ubiquitous overexpression of NANOG in mice causes hyperplasia selectively in the oesophagus, in association with increased cell proliferation. NANOG transcriptionally activates the mitotic programme, including Aurora A kinase (Aurka), in stratified epithelia, and endogenous NANOG directly binds to the Aurka promoter in primary keratinocytes. Interestingly, overexpression of Nanog or Aurka in mice increased proliferation and aneuploidy in the oesophageal basal epithelium. Finally, inactivation of NANOG in cell lines from oesophageal or head and neck squamous cell carcinomas (ESCCs or HNSCCs, respectively) results in lower levels of AURKA and decreased proliferation, and NANOG and AURKA expression are positively correlated in HNSCCs. Together, these results indicate that NANOG has a lineage-restricted mitogenic function in stratified epithelia.

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“…Maintenance of the pluripotent state depends on keeping Oct4 expression between upper and lower limits; loss of expression leads to trophectoderm differentiation [59,60] while a higher level induces differentiation to mesoderm and endoderm [60]. Sox2 is required for epiblast maintenance [61] and acts upon many of the same target genes as Oct4 by binding to DNA sequences adjacent to the Oct4 binding site [62]. The level of expression of Nanog determines self-renewal in mouse ES cells as overexpression renders the cells independent of cytokine [63]), while reduced expression causes a reduction in self-renewal efficiency [64].…”

Section: Mechanisms That Underpin Pluripotencymentioning

confidence: 99%

“…In contrast, new studies that monitor changes in thousands of genes and use bioinformatics tools to identify interactions between genes are revealing large networks of interactions [62,68]. Genome-wide chromatin immunoprecipitation (ChIP) has been used extensively to identify transcriptional networks.…”

Section: Mechanisms That Underpin Pluripotencymentioning

confidence: 99%

The evolving biology of cell reprogramming

Wilmut

Sullivan²,

Chambers³

2011

Phil. Trans. R. Soc. B

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Modern stem cell biology has achieved a transformation that was thought by many to be every bit as unattainable as the ancient alchemists' dream of transforming base metals into gold. Exciting opportunities arise from the process known as ‘cellular reprogramming’ in which cells can be reliably changed from one tissue type to another. This is enabling novel approaches to more deeply investigate the fundamental basis of cell identity. In addition, new opportunities have also been created to study (perhaps even to treat) human genetic and degenerative diseases. Specific cell types that are affected in inherited disease can now be generated from easily accessible cells from the patient and compared with equivalent cells from healthy donors. The differences in cellular phenotype between the two may then be identified, and assays developed to establish therapies that prevent the development or progression of disease symptoms. Cellular reprogramming also has the potential to create new cells to replace those whose death or dysfunction causes disease symptoms. For patients suffering from inherited cases of degenerative diseases like Parkinson's disease or amyotrophic lateral sclerosis (also known as motor neuron disease), the future realization of such cell-based therapies would truly be worth its weight in gold. However, before this enormous potential can become a reality, several significant biological and technical challenges must be overcome. Furthermore, to maintain the credibility of the scientific community with the general public, it is important that hope-inspiring advances are not over-hyped. The papers in this issue of the Philosophical Transactions of the Royal Society B : Biological Sciences cover many areas relevant to this topic. In this Introduction , we provide an overall context in which to consider these individual papers.

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The transcriptional foundation of pluripotency

Cited by 403 publications

References 83 publications

Negative autoregulation of Oct3/4 through Cdx1 promotes the onset of gastrulation

Negative autoregulation of Oct3/4 through Cdx1 promotes the onset of gastrulation

Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia

The evolving biology of cell reprogramming

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