REGULATORY GENOMICS:
Advanced
genomics instruments, technology and methods for determination
of transcription factor binding
specificities; applications for identification of genes
predisposing to colorectal cancer
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 of the REGULATORY GENOMICS
project:
1. To develop novel high throughput multiwell-plate and DNA-chip based methods
for determination of TF binding specificity
2. To experimentally determine the binding specificities of known cancer-associated
TFs
3. To computationally predict, and to experimentally verify, elements that are
regulated by these TFs in genes that are 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
Project
Coordinator:
