Objectif
Determination of the sequence of the human genome, and knowledge of the genetic code through which mRNA is translated have allowed rapid progress in identification of mammalian proteins. However, less is known about the molecular mechanisms that control expression of human genes, and about the variations in gene expression that underlie many pathological states, including cancer. This is caused in part by lack of information about the 'second genetic code' - binding specificities of transcription factors (TFs).Deciphering this regulatory code is critical for cancer research, as little is known about the mechanisms by which the known genetic defects induce the transcriptional programs that control cell proliferation, survival and angiogenesis. In addition, changes in binding of transcription factors caused by single nucleotide polymorphisms (SNPs) are likely to be a major factor in many quantitative trait conditions, including familial predisposition to cancer. We aim to develop novel genomics tools and methods for determination of transcription factor binding specificity. These tools will be used for identification of regulatory SNPs that predispose to colorectal cancer, and for characterization of downstream target genes that are common to multiple oncogenic TFs. Specific aims: 1. To develop novel high throughput multiwell-plate and DNA-chip based methods for determining TF binding specificity 2. To experimentally determine the binding specificities of known cancer-associated TFs 3. To computationally predict and experimentally verify elements regulated by these TFs in genes essential for cell proliferation. 4. To develop a SNP genotyping chip composed of SNPs that affect the function of TF-binding sites conserved in mammalian species. 5. To use this chip for genotyping of patients with hereditary cancer predisposition as well as controls in three European populations, for identification of regulatory SNPs associated with cancer.
Champ scientifique
Appel à propositions
FP6-2003-LIFESCIHEALTH-I
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