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.

Download full-text


Available from: Roshan Kumar, Sep 15, 2014
68 Reads
  • Source
    • "These seemingly contradictory phenotypes of OCT4 knockdown may underlie multiple roles for OCT4 in ES cell maintenance and differentiation . OCT4 is well known to repress differentiation genes (Boyer et al., 2005) such that lack of its expression leads to de-repression of these genes but at low levels without other differentiation induction signals. The second role of OCT4 that we uncovered is its involvement in the removal of PRC2 complex from mesendodermal genes and its requirement for the physiologic expression of these genes during directed differentiation of hES cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We demonstrate that the pluripotency gene OCT4 has a role in regulating differentiation via Wnt signaling. OCT4 expression levels in human embryonic stem cells increases transiently during the first 24 hr of in vitro differentiation, with OCT4 occupancy increasing at endoderm regulators such as SOX17 and FOXA2. This increased occupancy correlates with loss of the PRC2 complex and the inhibitory histone mark H3K27me3. Knockdown of OCT4 during differentiation inhibits mesendoderm formation and removal of the H3K27me3 mark from the SOX17 promoter, suggesting that OCT4 acts to induce removal of the PRC2 complex. Furthermore, OCT4 and β-catenin can be co-immunoprecipitated upon differentiation, and Wnt stimulation is required for the enhanced OCT4 occupancy and loss of the PRC2 complex from the SOX17 promoter. In conclusion, our study reveals that OCT4, a master regulator of pluripotency, may also collaborate with Wnt signaling to drive endoderm induction by pre-patterning epigenetic markers on endodermal promoters.
    Stem Cell Reports 09/2015; DOI:10.1016/j.stemcr.2015.08.014 · 5.37 Impact Factor
    • "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. "
    [Show abstract] [Hide abstract]
    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). "
    [Show abstract] [Hide abstract]
    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
Show more