Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA189961 | ENA |
REPOSITORIES: ENA
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Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells
A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation.
This model is described in the article:
In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.
Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R
BMC Genomics, 2009, 10:314
Abstract:
BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency.
RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation.
CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies.
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2005-01-01 | MODEL1305010000 | BioModels
Project description:Reprogramming of somatic cells into induced pluripotent stem cells (iPSC) is an epigenetic phenomenon. It has been suggested that iPSC retain some tissue-specific memory whereas little is known about inter-individual epigenetic variation of iPSC clones. In this study we have reprogrammed mesenchymal stromal cells (MSC) from human bone marrow by retrovirus-mediated overexpression of OCT-3/4, SOX2, c-MYC, and KLF4. Global DNA-methylation profiles of the initial MSC, MSC-derived iPSC (iP-MSC) and embryonic stem cells (ESC) were then compared using a high density DNA-methylation array covering more than 450,000 CpG sites. Overall, DNA-methylation patterns of iP-MSC and ESC were similar whereas some CpG sites revealed highly significant differences, which were not related to parental MSC. Furthermore, hypermethylation in iP-MSC versus ESC was particularly enriched in developmental genes as well as shore regions next to CpG islands indicating that these differences are not due to tissue-specific memory or random de novo methylation. Subsequently, we searched for CpG sites with donor-specific variation in MSC preparations. These “epigenetic fingerprints” were highly enriched in non-promoter regions and outside of CpG islands – and they were maintained upon reprogramming into iP-MSC. In conclusion, DNA methylation profiles of iP-MSC clones from the same donor were closely related despite heterogeneity of MSC. On the other hand, iP-MSC maintain donor-derived epigenetic differences. In the absence of isogenic controls for disease modeling applications, it would therefore be more appropriate to compare iPSC from different donors rather than a high number of different clones from the same patient.
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