Coherent functional modules improve transcription factor target identification, cooperativity prediction, and disease association.

• Main Authors: Konrad J Karczewski, Michael Snyder, Russ B Altman, Nicholas P Tatonetti
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2014-02-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC3916285?pdf=render

Transcription factors (TFs) are fundamental controllers of cellular regulation that function in a complex and combinatorial manner. Accurate identification of a transcription factor's targets is essential to understanding the role that factors play in disease biology. However, due to a high false positive rate, identifying coherent functional target sets is difficult. We have created an improved mapping of targets by integrating ChIP-Seq data with 423 functional modules derived from 9,395 human expression experiments. We identified 5,002 TF-module relationships, significantly improved TF target prediction, and found 30 high-confidence TF-TF associations, of which 14 are known. Importantly, we also connected TFs to diseases through these functional modules and identified 3,859 significant TF-disease relationships. As an example, we found a link between MEF2A and Crohn's disease, which we validated in an independent expression dataset. These results show the power of combining expression data and ChIP-Seq data to remove noise and better extract the associations between TFs, functional modules, and disease.