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It is essential to understand the network of transcription factors controlling self-renewal of human embryonic stem cells (ESCs) and human embryonal carcinoma cells (ECs) if we are to exploit these cells in regenerative medicine regimes. Correlating gene expression levels after RNAi-based ablation of OCT4 function with its downstream targets enables a better prediction of motif-specific driven expression modules pertinent for self-renewal and differentiation of embryonic stem cells and induced pluripotent stem cells.We initially identified putative direct downstream targets of OCT4 by employing CHIP-on-chip analysis. A comparison of three peak analysis programs revealed a refined list of OCT4 targets in the human EC cell line NCCIT, this list was then compared to previously published OCT4 CHIP-on-chip datasets derived from both ES and EC cells. We have verified an enriched POU-motif, discovered by a de novo approach, thus enabling us to define six distinct modules of OCT4 binding and regulation of its target genes.A selection of these targets has been validated, like NANOG, which harbours the evolutionarily conserved OCT4-SOX2 binding motif within its proximal promoter. Other validated targets, which do not harbour the classical HMG motif are USP44 and GADD45G, a key regulator of the cell cycle. Over-expression of GADD45G in NCCIT cells resulted in an enrichment and up-regulation of genes associated with the cell cycle (CDKN1B, CDKN1C, CDK6 and MAPK4) and developmental processes (BMP4, HAND1, EOMES, ID2, GATA4, GATA5, ISL1 and MSX1). A comparison of positively regulated OCT4 targets common to EC and ES cells identified genes such as NANOG, PHC1, USP44, SOX2, PHF17 and OCT4, thus further confirming their universal role in maintaining self-renewal in both cell types. Finally we have created a user-friendly database (http://biit.cs.ut.ee/escd/), integrating all OCT4 and stem cell related datasets in both human and mouse ES and EC cells.In the current era of systems biology driven research, we envisage that our integrated embryonic stem cell database will prove beneficial to the booming field of ES, iPS and cancer research.
Pubmed ID: 20505756 RIS Download
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Web server for functional enrichment analysis and conversions of gene lists. Web based tool for functional profiling of gene lists from large scale experiments. Has web interface with powerful visualization. Used for analyzing data from any organism.
View all literature mentionsRoche NimbleGen, Inc. is a leading innovator, manufacturer and supplier of a proprietary suite of DNA microarrays, consumables, instruments and services. Roche NimbleGen uniquely produces high-density arrays of long oligo probes that provide greater information content and higher data quality necessary for studying the full diversity of genomic and epigenomic variation. Roche NimbleGen is enabling a new era of High-Definition Genomics by providing scientists with cost-effective, high-throughput tools for extracting and integrating complex data on important forms of genomic and epigenomic variation not previously accessible on a genome-wide scale. Scientists can thus obtain a clearer understanding of genomic and epigenomic structure and function and how they impact biology and medicine. This improved performance is made possible by Roche NimbleGen''s proprietary Maskless Array Synthesis (MAS) technology, which uses digital light processing and rapid, high-yield photochemistry to synthesize long oligo, high-density DNA microarrays with extreme flexibility. NimbleGen Systems was established in 1999. The MAS technology is the result of research collaborations between the departments of biotechnology, genetics, physics, and semiconductor engineering at the University of Wisconsin - Madison. Roche NimbleGen has the exclusive worldwide license to the MAS technology from the Wisconsin Alumni Research Foundation (WARF).
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