Abstract
In the Saccharomyces cerevisiae pheromone-response pathway, the transcription factor Ste12 is inhibited by two mitogen-activated protein (MAP)-kinase-responsive regulators, Dig1 and Dig2. These two related proteins bind to distinct regions of Ste12 but are redundant in their inhibition of Ste12-dependent gene expression. Here we describe three functions for Dig1 that are non-redundant with those of Dig2. First, the removal of Dig1 results in a specific increase in intrinsic and extrinsic noise in the transcriptional outputs of the mating pathway. Second, in dig1Δ cells, Ste12 relocalizes from the nucleoplasmic distribution seen in wild-type cells into discrete subnuclear foci. Third, genome-wide insertional chromatin immunoprecipitation studies revealed that Ste12-dependent genes have increased interchromosomal interactions in dig1Δ cells. These findings suggest that the regulation of gene expression through long-range gene interactions, a widely observed phenomenon, comes at the cost of increased noise. Consequently, cells may have evolved mechanisms to suppress noise by controlling these interactions.
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Acknowledgements
We thank J. S. Weissman, E. K. O'Shea, J. E. Haber, W. A. Lim, A. D. Johnson and D. J. Sherratt for plasmids and protocols; C. D. Chun and P. D. Hartley for help in conducting and analysing the ChIP-chip experiments; W. F. Marshall and K. Wemmer for assistance with microscopy; and A. D. Johnson, S. Komili, W. F. Marshall and S. Shankar for helpful comments on the manuscript. This work was supported by a Genentech Fellowship and a National Science Foundation Predoctoral Fellowship to E.M., a National Institutes of Health (NIH) Ruth L. Kirschstein National Research Service Award to A.S., and funding from the University of California, San Francisco, Program for Breakthrough Biomedical Research and a NIH grant (R01 GM086379) to H.D.M. and H.E.-S.
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E.M. constructed all strains and performed and analysed all experiments except the fluorescence-activated cell sorting (FACS)-based mating assay. A.S. constructed strains for and performed the FACS-based mating assay. H.E.-S. and E.M. wrote custom MATLAB software and conducted data analyses for the FACS assays. E.M., H. E.-S. and H.D.M. wrote the manuscript.
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McCullagh, E., Seshan, A., El-Samad, H. et al. Coordinate control of gene expression noise and interchromosomal interactions in a MAP kinase pathway. Nat Cell Biol 12, 954–962 (2010). https://doi.org/10.1038/ncb2097
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DOI: https://doi.org/10.1038/ncb2097
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