Báo cáo khoa học: Seed-based systematic discovery of specific transcription factor target genes

Seed-based Systematic Discovery of Specific Transcription Factor Target Genes

Authors: Ralf Mrowka, Nils Blüthgen, Michael Fähling

Field: Systems Biology, Computational Physiology, Bioinformatics

Document Summary:

This research introduces a novel, systematic genome-wide approach, the “seed-distribution-distance method,” designed to enhance the accuracy of identifying specific transcription factor target genes. Traditional sequence-based methods often yield numerous false predictions due to short and degenerate DNA-binding motifs. The proposed method leverages large-scale genome-wide expression data to identify genes exhibiting similar expression patterns to known targets. By narrowing down the focus for sequence-based analysis, this approach significantly reduces false-positive predictions. The study demonstrates the method’s robustness through cross-validation, showcasing its ability to recover specific target genes and identify genes with characteristic functions and binding motifs. The method is exemplified by predicting new targets for the transcription factor NF-κB, including optineurin, a gene implicated in adult-onset primary open-angle glaucoma. Experimental validation confirms optineurin and other predicted genes as NF-κB targets, shedding light on NF-κB signaling and optineurin’s regulatory role.

Detailed Table of Contents:

• Keywords
• Correspondence
• Abstract
• Introduction
• Abbreviations
• Results
• The seed-distribution-distance method
• Top members in the rank show typical NF-κB functions
• High density of putative NF-kB DNA-binding sites in promoters in the top group of the rank
• Robustness of seed-distribution-distance method
• Enrichment of putative transcription factor binding sites in top group
• The list of predicted NF-kB targets and experimental verification
• Discussion
• When does the seed-distribution-distance method work?
• Reporter gene activity
• Gene ontology overrepresentation
• Acknowledgements
• References
• Supplementary material