Systematic Target Function Annotation of Human Transcription Factors

  • Posted on: 23 March 2016
  • By: fcoldren
TitleSystematic Target Function Annotation of Human Transcription Factors
Publication TypeWeb Article
Year of Publication2016
AuthorsLi YFuga, Altman RB
Series TitlearXiv
Other NumbersarXiv:1602.06591

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.