Inferring genome-wide functional modulatory network: a case study on NF-κB/RelA transcription factor

Area of Science:

• Molecular Biology
• Systems Biology
• Genomics

Background:

• Understanding context-specific transcriptional regulation by transcription factors (TFs) remains incomplete.
• Modulators can influence TF activity at the post-transcriptional level in a gene-specific manner, affecting activation or inhibition.

Purpose of the Study:

• To model context-specific transcriptional regulation using a network approach.
• To identify and characterize modulators of the transcription factor NF-κB/RelA and their action modes.

Main Methods:

• Development of a modulatory network model comprising TF, target gene, and modulator.
• Inference of potential modulators for NF-κB/RelA from large-scale expression profile data.

Main Results:

• Identified numerous novel proteins modulating NF-κB/RelA activity, including those involved in RNA processing, cell cycle, and proteolysis.
• Discovered that modulators from different biological processes exhibit specific action modes (enhancement, attenuation, inversion).
• Revealed distinct modulatory networks for NF-κB/RelA in epithelial-mesenchymal transition (EMT) and burn injury contexts, involving specific genes like FBN1, ACTN1, MALAT1, FOXP1, TXNIP, and GAPDH.

Conclusions:

• The modulatory network framework provides insights into context-specific TF regulation.
• NF-κB/RelA activity is fine-tuned by diverse modulators with specific functional roles and action modes.
• Context-dependent modulation of NF-κB/RelA highlights its complex role in biological processes and disease states.