The transcriptional & signalling networks of pluripotency

Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672, Singapore.
Nature Cell Biology (Impact Factor: 19.68). 05/2011; 13(5):490-6. DOI: 10.1038/ncb0511-490
Source: PubMed


Pluripotency and self-renewal are the hallmarks of embryonic stem cells. This state is maintained by a network of transcription factors and is influenced by specific signalling pathways. Current evidence indicates that multiple pluripotent states can exist in vitro. Here we review the recent advances in studying the transcriptional regulatory networks that define pluripotency, and elaborate on how manipulation of signalling pathways can modulate pluripotent states to varying degrees.

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    • "The comprehensive database of expression profiles of protein-coding genes implicated in the development of the fetal and adult brain of H. sapiens was obtained from the previously published contribution (Zhang et al., 2011). Analysis of the evolutionary age of genes comprising the 4,958-gene expression signature of the neocortex/prefrontal cortex regions of human brain was carried-out by segregating genes into thirteen sub-groups based on their respective evolutionary age, ranging from 0 (oldest genes) to 12 (youngest genes) as previously defined by Zhang et al. (2011). The gene expression enrichment factors were calculated for each individual evolutionary age sub-group by comparisons of corresponding gene age-associated distribution metrics, which were derived from the analysis of gene age-associated distribution profiles of all 19,335 genes interrogated in gene expression profiling experiments and 12,885 genes with expression changes significantly different in fetal versus adult brain. "
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    ABSTRACT: Genome-wide proximity placement analysis of 10,598 HSGRL within the context of the principal regulatory structures of the interphase chromatin, namely topologically-associating domains (TADs) and specific sub-TAD structures termed super-enhancer domains (SEDs) revealed that 0.8%-10.3% of TADs contain more than half of HSGRL. Of the 3,127 TADs in the hESC genome, 24 (0.8%); 53 (1.7%); 259 (8.3%); and 322 (10.3%) harbor 1,110 (52.4%); 1,936 (50.9%); 1,151 (59.6%); and 1,601 (58.3%) HSGRL sequences from four distinct families, respectively. TADs that are enriched for HSGRL and termed rapidly-evolving in humans TADs (revTADs) manifest distinct correlation patterns between HSGRL placements and recombination rates. There are significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (p < 0.0001 in all instances). In hESC genome, 331 of 504 (66%) of SE-harboring TADs contain HSGRL and 68% of SEs co-localize with HSGRL, suggesting that HSGRL rewired SE-driven GRNs within revTADs by inserting novel and/or erasing existing regulatory sequences. Consequently, markedly distinct features of chromatin structures evolved in hESC compared to mouse: the SE quantity is 3-fold higher and the median SE size is significantly larger; concomitantly, the TAD number is increased by 42% while the median TAD size is decreased (p=9.11E-37). Present analyses revealed a global role for HSGRL in increasing both quantity and size of SEs and increasing the number and size reduction of TADs, which may facilitate a convergence of TAD and SED architectures of interphase chromatin and define a trend of increasing regulatory complexity during evolution of GRNs.
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    • "An examination of the pattern of transcription factor binding to superenhancer constituents provided a hypothesis to resolve this conundrum (Figure 3A, Table S3). The terminal TFs of the Wnt (TCF3), TGF-b (SMAD3), and LIF (STAT3) signaling pathways, which play essential roles in transcriptional control of the stem cell state (Ng and Surani, 2011; Young, 2011), were among the TFs whose binding pattern to SE constituents was most similar to that of OCT4, SOX2, and NANOG at SE constituents (Figure 3A). Most SE constituents (75%) were occupied by at least one of these three TFs, whereas only 43% of typical enhancer constituents were bound by one of the three (Figure S3A). "
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    ABSTRACT: Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here, we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 03/2015; 58(2). DOI:10.1016/j.molcel.2015.02.014 · 14.02 Impact Factor
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    • "Several studies have reported that after transgenic interventions , hESCs/iPSCs with naive properties can be derived and maintained (Buecker et al., 2010; Hanna et al., 2010; Wang et al., 2011). However, the requirement for continued genetic manipulation limits their clinical utility and it is desirable to identify culture conditions that directly support human naive pluripotency independently of transgenes. "
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    ABSTRACT: Pluripotency is the remarkable capacity of a single cell to engender all the specialized cell types of an adult organism. This property can be captured indefinitely through derivation of self-renewing embryonic stem cells (ESCs), which represent an invaluable platform to investigate cell fate decisions and disease. Recent advances have revealed that manipulation of distinct signaling cues can render ESCs in a uniform "ground state" of pluripotency, which more closely recapitulates the pluripotent naive epiblast. Here we discuss the extrinsic and intrinsic regulatory principles that underpin the nature of pluripotency and consider the emerging spectrum of pluripotent states.
    Cell Stem Cell 10/2014; 15(4):416-430. DOI:10.1016/j.stem.2014.09.015 · 22.27 Impact Factor
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