Unraveling transcriptional regulatory programs by integrative analysis of microarray and transcription factor binding data
Open Access
- 27 June 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Bioinformatics
- Vol. 24 (17), 1874-1880
- https://doi.org/10.1093/bioinformatics/btn332
Abstract
Motivation: Unraveling the transcriptional regulatory program mediated by transcription factors (TFs) is a fundamental objective of computational biology, yet still remains a challenge. Method: Here, we present a new methodology that integrates microarray and TF binding data for unraveling transcriptional regulatory networks. The algorithm is based on a two-stage constrained matrix decomposition model. The model takes into account the non-linear structure in gene expression data, particularly in the TF-target gene interactions and the combinatorial nature of gene regulation by TFs. The gene expression profile is modeled as a linear weighted combination of the activity profiles of a set of TFs. The TF activity profiles are deduced from the expression levels of TF target genes, instead directly from TFs themselves. The TF-target gene relationships are derived from ChIP-chip and other TF binding data. The proposed algorithm can not only identify transcriptional modules, but also reveal regulatory programs of which TFs control which target genes in which specific ways (either activating or inhibiting). Results: In comparison with other methods, our algorithm identifies biologically more meaningful transcriptional modules relating to specific TFs. We applied the new algorithm on yeast cell cycle and stress response data. While known transcriptional regulations were confirmed, novel TF-gene interactions were predicted and provide new insights into the regulatory mechanisms of the cell. Contact:zhanmi@mail.nih.gov Supplementary information: Supplementary data are available at Bioinformatics online.Keywords
This publication has 42 references indexed in Scilit:
- Systematic identification of cell cycle regulated transcription factors from microarray time series dataBMC Genomics, 2008
- Deciphering modular and dynamic behaviors of transcriptional networksGenomic Medicine, 2007
- GeneTrail--advanced gene set enrichment analysisNucleic Acids Research, 2007
- The discovery of transcriptional modules by a two-stage matrix decomposition approachBioinformatics, 2006
- Identification of regulatory modules by co-clustering latent variable models: stem cell differentiationBioinformatics, 2006
- Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction NetworksGenome Research, 2003
- Network Motifs: Simple Building Blocks of Complex NetworksScience, 2002
- Computational Identification of Transcription Factor Binding Sites via a Transcription-factor-centric Clustering (TFCC) AlgorithmJournal of Molecular Biology, 2002
- Computational identification of Cis-regulatory elements associated with groups of functionally related genes in Saccharomyces cerevisiaeJournal of Molecular Biology, 2000
- Activation of heat shock transcription factor 1 to a DNA binding form during the G1phase of the cell cycleCell Stress and Chaperones, 1999