Beyond microarrays: find key transcription factors controlling signal transduction pathways.
BACKGROUND
Massive gene expression changes in different cellular states measured by microarrays, in fact, reflect just an "echo" of real molecular processes in the cells. Transcription factors constitute a class of the regulatory molecules that typically require posttranscriptional modifications or ligand binding in order to exert their function. Therefore, such important functional changes of transcription factors are not directly visible in the microarray experiments.


RESULTS
We developed a novel approach to find key transcription factors that may explain concerted expression changes of specific components of the signal transduction network. The approach aims at revealing evidence of positive feedback loops in the signal transduction circuits through activation of pathway-specific transcription factors. We demonstrate that promoters of genes encoding components of many known signal transduction pathways are enriched by binding sites of those transcription factors that are endpoints of the considered pathways. Application of the approach to the microarray gene expression data on TNF-alpha stimulated primary human endothelial cells helped to reveal novel key transcription factors potentially involved in the regulation of the signal transduction pathways of the cells.


CONCLUSIONS
We developed a novel computational approach for revealing key transcription factors by knowledge-based analysis of gene expression data with the help of databases on gene regulatory networks (TRANSFAC and TRANSPATH. The corresponding software and databases are available at http://www.gene-regulation.com.
Kel
Alexdander
A
BIOBASE GmbH, Halchtersche Str, 33, D-38304 Wolfenbüttel, Germany. alexander.kel@biobase-international.com
Voss
Nico
N
Jauregui
Ruy
R
Kel-Margoulis
Olga
O
Wingender
Edgar
E
D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D030561:Databases, Nucleic Acid; D042783:Endothelial Cells / Q000378:metabolism; D053263:Gene Regulatory Networks; D006801:Humans; D020407:Internet; D046228:Microarray Analysis; D015398:Signal Transduction; D014157:Transcription Factors / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic
D014157:Transcription Factors