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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    • "Moreover, all cells stained positive for the pluripotency markers OCT4 and SSEA-1 irrespective of their " high " or " low " miR-142 state identities (Fig EV3C and D). Additional pluripotency markers (Ng & Surani, 2011) showed no significant difference at the mRNA expression levels (Fig EV3E). In addition, neither " high " nor " low " miR-142 state cells shared molecular markers with epiblast stem cells (Fig EV3F), that reside in a state of primed pluripotency. "

    Preview · Article · Dec 2015 · Molecular Systems Biology
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    • "Cells such as embryonic stem (ES) cells that retain selfrenewal potential and multipotency only in vitro can also be included in the category of stem cells. Such stemness of ES cells is thought to be maintained by formation of a core transcriptional network and an epigenetic status unique to ES cells (Lund et al., 2012; Meissner, 2010; Ng and Surani, 2011). A stem cell equivalent to ES cells, called induced pluripotent stem (iPS) cells, can be produced from somatic cells by overexpression of only a few specific transcription factors (OCT3/4, SOX2, KLF4, and C-MYC), which are thought to be the essential components in forming the core network of transcriptional factors that define the status of ES cells (Takahashi et al., 2007; Takahashi and Yamanaka, 2006; Yamanaka, 2012). "
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    ABSTRACT: Self-renewal potential and multipotency are hallmarks of a stem cell. It is generally accepted that acquisition of such stemness requires rejuvenation of somatic cells through reprogramming of their genetic and epigenetic status. We show here that a simple block of cell differentiation is sufficient to induce and maintain stem cells. By overexpression of the transcriptional inhibitor ID3 in murine hematopoietic progenitor cells and cultivation under B cell induction conditions, the cells undergo developmental arrest and enter a self-renewal cycle. These cells can be maintained in vitro almost indefinitely, and the long-term cultured cells exhibit robust multi-lineage reconstitution when transferred into irradiated mice. These cells can be cloned and re-expanded with 50% plating efficiency, indicating that virtually all cells are self-renewing. Equivalent progenitors were produced from human cord blood stem cells, and these will ultimately be useful as a source of cells for immune cell therapy.
    Full-text · Article · Oct 2015 · Stem Cell Reports
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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.
    Preview · Article · Jul 2015
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