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Intercalation of a new tier of transcription regulation into an ancient circuit

Nature volume 468, pages 959–963 (2010)Cite this article

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Abstract

Changes in gene regulatory networks are a major source of evolutionary novelty1,2,3. Here we describe a specific type of network rewiring event, one that intercalates a new level of transcriptional control into an ancient circuit. We deduce that, over evolutionary time, the direct ancestral connections between a regulator and its target genes were broken and replaced by indirect connections, preserving the overall logic of the ancestral circuit but producing a new behaviour. The example was uncovered through a series of experiments in three ascomycete yeasts: the bakers’ yeast Saccharomyces cerevisiae, the dairy yeast Kluyveromyces lactis and the human pathogen Candida albicans. All three species have three cell types: two mating-competent cell forms (a and α) and the product of their mating (a/α), which is mating-incompetent. In the ancestral mating circuit, two homeodomain proteins, Mata1 and Matα2, form a heterodimer that directly represses four genes that are expressed only in a and α cells and are required for mating4,5,6. In a relatively recent ancestor of K. lactis, a reorganization occurred. The Mata1–Matα2 heterodimer represses the same four genes (known as the core haploid-specific genes) but now does so indirectly through an intermediate regulatory protein, Rme1. The overall logic of the ancestral circuit is preserved (haploid-specific genes ON in a and α cells and OFF in a/α cells), but a new phenotype was produced by the rewiring: unlike S. cerevisiae and C. albicans, K. lactis integrates nutritional signals, by means of Rme1, into the decision of whether or not to mate.

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Figure 1: The core hsgs are not directly regulated by a1–α2 in K. lactis.
Figure 2: RME1 is a direct activator of hsg expression and is required for K. lactis mating.
Figure 3: Overexpression of RME1 is sufficient for hsg expression in the absence of nutrient starvation.
Figure 4: A simplified model for the evolution of regulation of core hsgs in three yeasts.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The gene expression array data have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE24874. For the ChIP-chip data the accession number is GSE25209.

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Acknowledgements

We thank Q. Mitrovich, O. Homann, A. Hernday, M. Miller, C. Cain, T. Sorrells and H. Madhani for helpful discussions and technical contributions; and S. Åström for generously providing the K. lactis strains used in this study. The S. cerevisiae strains were a gift from the H. Madhani and J. Li laboratories. The work was funded by grant RO1 GM037049 from the National Institutes of Health. L.N.B. is a National Science Foundation Graduate Research Fellow.

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  1. Brian B. Tuch

    Present address: Present address: Genome Analysis Unit, Amgen, South San Francisco, California 94080, USA.,

Authors and Affiliations

  1. Department of Microbiology and Immunology and Department of Biochemistry and Biophysics, University of California, San Francisco, 94158, California, USA

    Lauren N. Booth, Brian B. Tuch & Alexander D. Johnson

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Contributions

L.N.B. performed all experiments. L.N.B. and B.B.T. analysed data. L.N.B., B.B.T. and A.D.J. designed the study and wrote the paper.

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Correspondence to Alexander D. Johnson.

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Booth, L., Tuch, B. & Johnson, A. Intercalation of a new tier of transcription regulation into an ancient circuit. Nature 468, 959–963 (2010). https://doi.org/10.1038/nature09560

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