  Transcription factors (TFs), the key players in transcriptional regulation,
have attracted great experimental attention, yet the functions of most human
TFs remain poorly understood. Recent capabilities in genome-wide protein
binding profiling have stimulated systematic studies of the hierarchical
organization of human gene regulatory network and DNA-binding specificity of
TFs, shedding light on combinatorial gene regulation. We show here that these
data also enable a systematic annotation of the biological functions and
functional diversity of TFs. We compiled a human gene regulatory network for
384 TFs covering the 146,096 TF-target gene relationships, extracted from over
850 ChIP-seq experiments as well as the literature. By integrating this network
of TF-TF and TF-target gene relationships with 3,715 functional concepts from
six sources of gene function annotations, we obtained over 9,000 confident
functional annotations for 279 TFs. We observe extensive connectivity between
transcription factors and Mendelian diseases, GWAS phenotypes, and
pharmacogenetic pathways. Further, we show that transcription factors link
apparently unrelated functions, even when the two functions do not share common
genes. Finally, we analyze the pleiotropic functions of TFs and suggest that
increased number of upstream regulators contributes to the functional
pleiotropy of TFs. Our computational approach is complementary to focused
experimental studies on TF functions, and the resulting knowledge can guide
experimental design for discovering the unknown roles of TFs in human disease
and drug response.
