Genetic Analysis of Variation in Transcription Factor Binding in Yeast

Variation in transcriptional regulation is thought to be a major cause of phenotypic diversity1,2. Although widespread differences in gene expression among individuals of a species have been observed3-8, few studies have examined the variability of transcription factor (TF) binding, and thus the extent and underlying genetic basis of TF binding diversity is largely unknown. In this study, we mapped differences in transcription binding among individuals and elucidated the genetic basis of such variation on a genome-wide scale. Whole-genome Ste12 binding profiles were determined using ChIP Seq in pheromone-treated cells of 43 segregants of a cross between two highly diverged yeast strains and their parental lines. We identified extensive Ste12 binding variation among individuals and mapped underlying cis- and trans- acting loci responsible for such variation. We showed that the majority of TF binding variation is cis-linked and that many variations are associated with polymorphisms residing in the binding motifs of Ste12 as well as those of several proposed Ste12 cofactors. We also identified two trans factors, AMN1 and FLO8, that modulate Ste12 binding to promoters of more than 10 genes under α-factor treatment. Neither of these two genes was known to regulate Ste12 previously, and we suggest that they may be mediators of gene activity and phenotypic diversity. Ste12 binding strongly correlates with gene expression for more than 200 genes indicating that binding variation is functional. Many of the variable bound genes are involved in cell wall organization and biogenesis. Overall these studies identified genetic regulators of molecular diversity among individuals and provide novel insights into mechanisms of gene regulation.