Cancer Research - Europa

Regulatory Genomics
Advanced Genomics Instruments,
Technology and Methods for
Determination of Transcription Factor
Binding Specialities; Applications
for Identifi cation of Genes Predisposing
to Colorectal Cancer
Summary
Determination of the sequence of the human genome, and
knowledge of the genetic code through which mRNA is
translated, have allowed rapid progress in the identifi cation
of mammalian proteins. However, less is known about the
molecular mechanisms that control the expression of genes.
This project sets out to address this problem by developing
novel tools and methods for analysing the specifi city of transcription
factors to bind to particular sequences of DNA.
Problem
Not enough 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 a lack of
information about the second genetic code – binding specifi
cities 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.
Aim
The objective is to develop novel genomics tools and methods
for the determination of transcription factor binding specifi
city. These tools will be used for the identifi cation of
regulatory SNPs that predispose to colorectal cancer, and
for characterisation of downstream target genes that are
common to multiple oncogenic TFs.
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Keywords | Genomics | molecular genetics | transcription factors |
The specifi c aims are:
• to develop novel high throughput multiwell-plate and
DNA-chipbased methods for determination of TF binding
specifi city;
• to determine experimentally the binding specifi cities of
known cancer- associated TFs;
• to predict computationally, and to verify experimentally,
elements that are regulated by these TFs in genes that
are essential for cell proliferation;
• to develop a SNP genotyping chip composed of SNPs
that aff ect the function of TF-binding sites conserved in
mammalian species;
• to use this chip for the genotyping of patients with
hereditary cancer predisposition as well as controls in
three European populations, for identifi cation of regulatory
SNPs associated with cancer.
Expected results
This project aims to understand the basic principles involved
in growth regulation by oncogenic TFs, and is expected to
have a major impact in the understanding of cancer. Identifi -
cation of SNPs associated with low penetrance cancer
predisposition would be a major breakthrough in the eff ort
to understand inheritance of quantitative trait loci, and will
have implications on the population’s healthcare.
The methods developed within the project ( 1) have already
allowed genome-scale prediction of regulatory elements in
the human genome, and the methods developed should
make feasible the analysis of DNAbinding specifi cities of
all TFs, and consequently signifi cantly improve our understanding
regulation of gene expression.
Potential applications
We expect that the project will lead to the identifi cation of
genes that associate with colorectal cancer. This will have
direct implications on diagnosis and treatment of a cancer
type that aff ects more than 200 000 Europeans every year.
Methods, tools and instrumentation for advanced genomics
developed within this project will improve EU scientifi c competitiveness
in the rapidly developing fi eld of regulatory
genomics, and will allow EU scientists to be in a very good
starting position to decipher the genetic code controlling
regulation of gene expression.
(1) Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E, Taipale J,
Genomewide Prediction of Mammalian Enhancers Based on Analysis of Transcription-
Factor Binding Affi nity. Cell. 124:47-59, 2006.
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME