MPI für molekulare Genetik / Department of Computational Molecular Biology |
|In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.|
|Authors:||Chavez, Lukas; Bais, Abha S; Vingron, Martin; Lehrach, Hans; Adjaye, James; Herwig, Ralf|
|Research Context:||he work was funded by the EU within its 7th Framework Programme with the grant APO-SYS (HEALTH-F4-2007-200767), the German Ministry of Science within its National Genome Research Network (NGFN-Plus, FKZ01GS08111), the BMBF programme (Cell-based Regenerative Medicine-01GN0530) and the Max Planck Society.|
|Date of Publication (YYYY-MM-DD):||2009-07-15|
|Title of Journal:||BMC Genomics|
|Journal Abbrev.:||BMC Genomics|
|Copyright:||2009 Chavez et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
|Review Status:||not specified|
|Abstract / Description:||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.
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.
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.
|Comment of the Author/Creator:||corresponding author email:
We thank Sean O' Keefe, Stefan Haas and Szymon Kielbasa for help in promoter sequence analysis.
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2164/10/314
|External Publication Status:||published|
|Communicated by:||Martin Vingron|
|Affiliations:||MPI für molekulare Genetik|