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Mol Syst Biol. 2009;5:327. doi: 10.1038/msb.2009.84. Epub 2009 Nov 17.

Dissection of a complex transcriptional response using genome-wide transcriptional modelling.

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  • 1Department of Molecular Heamatology and Cancer Biology, UCL Institute of Child Health, London, UK.


Modern genomics technologies generate huge data sets creating a demand for systems level, experimentally verified, analysis techniques. We examined the transcriptional response to DNA damage in a human T cell line (MOLT4) using microarrays. By measuring both mRNA accumulation and degradation over a short time course, we were able to construct a mechanistic model of the transcriptional response. The model predicted three dominant transcriptional activity profiles-an early response controlled by NFkappaB and c-Jun, a delayed response controlled by p53, and a late response related to cell cycle re-entry. The method also identified, with defined confidence limits, the transcriptional targets associated with each activity. Experimental inhibition of NFkappaB, c-Jun and p53 confirmed that target predictions were accurate. Model predictions directly explained 70% of the 200 most significantly upregulated genes in the DNA-damage response. Genome-wide transcriptional modelling (GWTM) requires no prior knowledge of either transcription factors or their targets. GWTM is an economical and effective method for identifying the main transcriptional activators in a complex response and confidently predicting their targets.

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