Office
of Biological and Environmental Research
DOE
Lowdose Radiation Program Workshop IV
Abstract
Title:
Genome-scale modeling of low-dose radiation responses
using microarray-based gene networks.
Authors: MA Coleman1, T Cricthlow21, D Nelson1,
L Peterson3 and AJ. Wyrobek1,
Institutions: 1Biology
and Biotechnology Research Program. 2 Center for Applied
Scientific Computing, Lawrence Livermore National Laboratory,
Livermore, CA. 94551. 3Departments of Medicine, Molecular
and Human Genetics, and Urology, Baylor College of Medicine,
Houston, TX 77030.
The identification and characterization of regulatory elements
of ionizing radiation (IR)- responsive genes can provide valuable
understanding of the genetic mechanisms of IRresponse. Groups
of genes with apparently different functions have been shown
to have similar IR response patterns. Similar radiation response
phenotypes are predicted to have common IR-induced gene expression
profiles that are controlled by shared groups of regulatory
elements. Using gene expression microarray data in conjunction
with tools developed for DNA sequence/pattern recognition
we have built a gene-network model that groups promoters and
identifies their regulatory elements that control differential
aspects of cellular responses to IR. Our model used differential
IR radiation responses to varying doses between 1 cGy and
400 cGy to identify known effector genes of the TP53 damage
sensing/signaling pathway that share the following common
transcription factor binding sites (TAFs): EGR, ETS, MAZ,
MZ1, SP1, and ZBP. Combinations of TAFs can be grouped into
modules that define the IR-responsive promoter. In the case
of the TP53- damage sensing pathway, different combination
of the regulatory elements EGRF-ETSMAZF-
ZBPF and their relative locations to each other were found
to be conserved among modulated genes such as: GADD45A, CDKN1A,
PCNA. The shared promoter
elements identified in silico is conserved across species
such as human and mouse,
suggesting common mechanisms of IR-responses. This model is
now applicable to
identify novel IR-modulated genes based solely on TAF homology
searching. Data to
identify genes/pathways that are associated with different
radiation response phenotypes (e.g., low dose sensitivity,
adaptive response, sensitivity to chromosome damage, etc.)
will require larger data sets that account for dose, time,
tissue specificity and genetic variation. The identification
and characterization of regulatory elements of IR-responsive
genes will provide powerful biological indicators of genetic
susceptibilities for tissue and genetic damage.
This
work was performed under the auspices of the U.S. Department
of Energy by the University of California, Lawrence Livermore
National Laboratory under
Contract No. W-7405-Eng-48 with funding from the DOE Low Dose
Radiation Research Program.
