Human Gene-Centered Transcription Factor Networks for Enhancers and Disease Variants

• Published in: Cell Vol. 161; no. 3; pp. 661 - 673
• Main Authors: Fuxman Bass, Juan I., Sahni, Nidhi, Shrestha, Shaleen, Garcia-Gonzalez, Aurian, Mori, Akihiro, Bhat, Numana, Yi, Song, Hill, David E., Vidal, Marc, Walhout, Albertha J.M.
• Format: Journal Article
• Language: English
• Published: United States 23.04.2015
• Subjects: Disease - genetics; Enhancer Elements, Genetic; gene expression regulation; Gene Regulatory Networks; genome; Genome-Wide Association Study; Humans; loci; mutants; Mutation; physiology; transcription factors; Transcription Factors - metabolism; Two-Hybrid System Techniques; yeasts
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.03.003

Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping methods test one TF at a time and require the use of cells harboring the mutation(s) of interest, they are not suitable to identify TFs that bind to wild-type and mutant loci. Here, we use gene-centered yeast one-hybrid (eY1H) assays to interrogate binding of 1,086 human TFs to 246 enhancers, as well as to 109 non-coding disease mutations. We detect both loss and gain of TF interactions with mutant loci that are concordant with target gene expression changes. This work establishes eY1H assays as a powerful addition to the toolkit of mapping human GRNs and for the high-throughput characterization of genomic variants that are rapidly being identified by genome-wide association studies.