Systematic target function annotation of human transcription factors

Area of Science:

• Genomics
• Systems Biology
• Bioinformatics

Background:

• Transcription factors (TFs) regulate gene expression, but most human TF functions are unknown.
• Genome-wide profiling advances enable systematic study of gene regulatory networks and TF DNA-binding specificity.
• These data can systematically annotate TF biological functions and diversity.

Purpose of the Study:

• To systematically annotate the biological functions and functional diversity of human transcription factors.
• To build a comprehensive human gene regulatory network and integrate it with functional annotations.
• To explore TF connections to diseases and functional pathways.

Main Methods:

• Compiled a human gene regulatory network for 384 TFs, including 146,096 TF-target gene relationships from ChIP-seq and literature.
• Integrated TF-TF and TF-target gene networks with 3715 functional concepts from six annotation sources.
• Analyzed TF connectivity to Mendelian diseases, GWAS phenotypes, and pharmacogenetic pathways.

Main Results:

• Obtained over 9000 confident functional annotations for 279 TFs.
• Observed extensive connectivity between TFs and Mendelian diseases, GWAS phenotypes, and pharmacogenetic pathways.
• Demonstrated that TFs link unrelated functions and analyzed TF pleiotropy, linking it to upstream regulators.

Conclusions:

• The computational approach complements experimental TF studies.
• The generated knowledge base can guide experimental design for discovering unknown TF roles.
• This work aids in understanding TF involvement in human disease and drug response.