title: Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets.
abstract: Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027; Department of Systems Biology, Columbia University, New York, NY 10032;
authors.forename: Mina
authors.initials: M
authors.lastname: Fazlollahi
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027;
authors.forename: Ivor
authors.initials: I
authors.lastname: Muroff
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027;
authors.forename: Eunjee
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032 hc2415@cumc.columbia.edu hjb2004@columbia.edu.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Causton
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027; Department of Systems Biology, Columbia University, New York, NY 10032; hc2415@cumc.columbia.edu hjb2004@columbia.edu.
authors.forename: Harmen J
authors.initials: HJ
authors.lastname: Bussemaker
mesh_terms: D000465:Algorithms; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D049770:Genes, Mating Type, Fungal / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C102298:DIG2 protein, S cerevisiae; C501391:GCN4 protein, S cerevisiae; C489241:STE12 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors
keywords: cofactor interactions; genetic variation in gene expression; quantitative trait locus mapping; transcription factors