UBIQUITOUS FUNCTIONAL SYNERGY PARTIALLY EXPLAINS WHY MOST TRANSCRIPTION FACTOR BINDING IS NON-FUNCTIONAL

Area of Science:

• Molecular Biology
• Systems Biology
• Genetics

Background:

• Transcription factors (TFs) regulate gene expression by binding to promoter regions.
• Predicting gene expression changes based on TF binding alone is challenging, as most bound genes do not alter expression upon TF perturbation.

Purpose of the Study:

• To investigate the phenomenon of functional synergy, where the presence of other TFs at a promoter influences a TF's effect on gene expression.
• To develop a predictive model for gene response to TF perturbation.

Main Methods:

• Created a comprehensive dataset of TF binding locations in yeast using a novel, orthogonal method.
• Employed mathematical modeling to identify instances of functional synergy from the dataset.

Main Results:

• Functional synergy is a common occurrence, affecting responses to 44 different TFs.
• 48 TFs acted as modifiers, with some TFs modifying the effects of numerous others.
• The study identified high-confidence instances of functional synergy.

Conclusions:

• TF binding location data alone is insufficient to determine gene regulation.
• Gene regulatory network models need enhancement to incorporate the modifying effects of TFs on each other.