title: Human gene-centered transcription factor networks for enhancers and disease variants.
abstract: 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.
authors.affiliation: Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Fuxman Bass
authors.affiliation: Department of Cancer Biology, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.affiliation: Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Shaleen
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Aurian
authors.initials: A
authors.lastname: Garcia-Gonzalez
authors.affiliation: Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mori
authors.affiliation: Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Numana
authors.initials: N
authors.lastname: Bhat
authors.affiliation: Department of Cancer Biology, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Cancer Biology, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Department of Cancer Biology, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Cancer Biology, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: marian.walhout@umassmed.edu.
authors.forename: Albertha J M
authors.initials: AJM
authors.lastname: Walhout
mesh_terms: D004194:Disease / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation; D014157:Transcription Factors / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D014157:Transcription Factors