Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells

Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Cell (Impact Factor: 32.24). 10/2005; 122(6):947-56. DOI: 10.1016/j.cell.2005.08.020
Source: PubMed


The transcription factors OCT4, SOX2, and NANOG have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES) cells in culture. To gain insights into transcriptional regulation of human ES cells, we have identified OCT4, SOX2, and NANOG target genes using genome-scale location analysis. We found, surprisingly, that OCT4, SOX2, and NANOG co-occupy a substantial portion of their target genes. These target genes frequently encode transcription factors, many of which are developmentally important homeodomain proteins. Our data also indicate that OCT4, SOX2, and NANOG collaborate to form regulatory circuitry consisting of autoregulatory and feedforward loops. These results provide new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal.

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Available from: Roshan Kumar, Sep 15, 2014
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    • "Oct4 is a nuclear transcription factor of the POU-homeodomain family that plays a critical role in several aspects of ESC maintenance including ESC self-renewal, pluripotency and lineage commitment [6] [7] [8]. At the top of the primitive pluripotent cell genetic regulatory network , Oct4 and SOX-2 function cooperatively to stimulate the transcription of several target genes including Nanog, FGF-4, UTFl, Fbx15, microRNA-302 clusters and even SOX-2 and Oct4 themselves [12] [13]. Consistent with their roles in maintaining pluripotency, overexpression of specific transcription factors (Oct4, SOX- 2, KLF4 and c-Myc) can induce somatic cells to acquire pluripotency. "
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    ABSTRACT: Expression of SOX-2 and Oct4 as markers for the identification of cancer stem cells (CSCs) has been revealed in several malignancies. In this study, the co-expression of SOX-2 and Oct4 and their correlation with clinicopathological features of endometrial adenocarcinomas (EACs) was investigated. SOX-2 and Oct4 expression was assessed by immunohistochemistry in 27 (39.13%) stage IA and in 42 (60.87%) stage IB International Federation of Gynaecology and Obstetrics (FIGO) EACs and related to the clinicopathological features of patients. The expression of SOX-2 was confirmed in 62/69 tumour specimens compared to Oct4 expression in 46/69 specimens (P = 0.015) and no difference in median staining intensity between SOX-2 and Oct-4 was observed. The highest median SOX-2 expression was found in high-grade (G3) EAC samples compared to moderate-grade (G2) EAC specimens (P = 0.020) and low-grade (G1) specimens (P = 0.008), while no differences in median Oct4 expression in EAC samples according to grading were present. In G3 specimens, significantly higher median SOX-2 expression was noted compared to Oct4 (P = 0.002). SOX-2 and Oct4 co-expression was observed only in G1 EAC (R: 0.51; P = 0.031). Age of EAC diagnosis was positively correlated with SOX-2 expression (b = 0.193; R(2) = 10.83%; P = 0.003) but not to age of menarche, menopause, parity or body mass index. There is no need to use SOX-2 expression as a poor outcome predictor in stage I EAC, and SOX-2 expression should be analysed in more advanced stages.
    International journal of clinical and experimental pathology 09/2015; 8(7):8189-98. · 1.89 Impact Factor
    • "To identify stemness-related markers on spheres we tested the expression of diverse pluripotency-related factors. Constitutive expression of SOX2 maintains cellular self-renewal, and coordinated with OCT4 and NANOG supports ESC-pluripotency (Boyer et al 2005). Furthermore, ectopic KLF4 expression reprogrammes pluripotency in somatic cells (Wei et al 2009). "
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    ABSTRACT: Osteosarcoma is a bone tumor displaying significant cellular and histological heterogeneity and a complex genetic phenotype. Although multiple studies strongly suggest the presence of cancer stem cells in osteosarcoma a consensus on their characterization is still missing. We used a combination of functional assays (sphere-forming, Aldefluor and side-population) for identification of cancer stem cell populations in osteosarcoma cell lines. Expression of stemness-related transcription factors, quiescent nature, in vivo tumorigenicity and Wnt/β-catenin activation were evaluated. We show that different cancer stem cell populations may co-exist in osteosarcoma cell lines exhibiting distinct functional properties. Osteosarcoma spheres are slowly-proliferating populations, overexpress SOX2 and KLF4 stemness-related genes and have enhanced tumorigenic potential. Additionally, spheres show specific activation of Wnt/β-catenin signaling as evidenced by increased nuclear β-catenin, TCF/LEF activity and AXIN2 expression, in a subset of the cell lines. Aldefluor-positive populations were detected in all osteosarcoma cell lines and overexpress SOX2, but not KLF4. The side-population phenotype is correlated with ABCG2 drug-efflux transporter expression. Distinct functional methods seem to identify cancer stem cells with dissimilar characteristics. Intrinsic heterogeneity may exist within osteosarcoma cancer stem cells and can have implications on the design of targeted therapies aiming to eradicate these cells within tumors.
    Journal of Cellular Physiology 09/2015; DOI:10.1002/jcp.25179 · 3.84 Impact Factor
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    • "We first compare two transcription networks from two different species that coordinate two different biological processes, but were deduced by similar methodologies. The network specifying the embryonic stem cell state (pluripotency) was chosen because it has been studied extensively by numerous labs and is supported by multiple studies (Boyer et al., 2005; Kim et al., 2008). For comparison, we chose the circuit controlling biofilm development in the pathogenic yeast C. albicans, a network this lab has studied extensively (Nobile et al., 2012). "
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    ABSTRACT: When transcription regulatory networks are compared among distantly related eukaryotes, a number of striking similarities are observed: a larger-than-expected number of genes, extensive overlapping connections, and an apparently high degree of functional redundancy. It is often assumed that the complexity of these networks represents optimized solutions, precisely sculpted by natural selection; their common features are often asserted to be adaptive. Here, we discuss support for an alternative hypothesis: the common structural features of transcription networks arise from evolutionary trajectories of "least resistance"-that is, the relative ease with which certain types of network structures are formed during their evolution. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 05/2015; 161(4):714-723. DOI:10.1016/j.cell.2015.04.014 · 32.24 Impact Factor
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