RESUMEN
In budding yeast, commitment to cell division corresponds to activating the positive feedback loop of G1 cyclins controlled by the transcription factors SBF and MBF. This pair of transcription factors has over 200 targets, implying that cell-cycle commitment coincides with genome-wide changes in transcription. Here, we find that genes within this regulon have a well-defined distribution of transcriptional activation times. Combinatorial use of SBF and MBF results in a logical OR function for gene expression and partially explains activation timing. Activation of G1 cyclin expression precedes the activation of the bulk of the G1/S regulon, ensuring that commitment to cell division occurs before large-scale changes in transcription. Furthermore, we find similar positive feedback-first regulation in the yeasts S. bayanus and S. cerevisiae, as well as human cells. The widespread use of the feedback-first motif in eukaryotic cell-cycle control, implemented by nonorthologous proteins, suggests its frequent deployment at cellular transitions.
Asunto(s)
Retroalimentación Fisiológica , Regulación Fúngica de la Expresión Génica , Genoma Fúngico , Saccharomyces cerevisiae/genética , Saccharomyces/genética , División Celular , Factores de Transcripción E2F/metabolismo , Factores de Transcripción E2F/fisiología , Regulación de la Expresión Génica , Células HeLa , Humanos , Modelos Genéticos , Regulón/fisiología , Saccharomyces/citología , Saccharomyces cerevisiae/citología , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiología , Activación TranscripcionalRESUMEN
The ability to specify and maintain discrete cell fates is essential for development. However, the dynamics underlying selection and stability of distinct cell types remain poorly understood. Here, we provide a quantitative single-cell analysis of commitment dynamics during the mating-mitosis switch in budding yeast. Commitment to division corresponds precisely to activating the G1 cyclin positive feedback loop in competition with the cyclin inhibitor Far1. Cyclin-dependent phosphorylation and inhibition of the mating pathway scaffold Ste5 are required to ensure exclusive expression of the mitotic transcriptional program after cell cycle commitment. Failure to commit exclusively results in coexpression of both cell cycle and pheromone-induced genes, and a morphologically mixed inviable cell fate. Thus, specification and maintenance of a cellular state are performed by distinct interactions, which are likely a consequence of disparate reaction rates and may be a general feature of the interlinked regulatory networks responsible for selecting cell fates.