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Yeast cell fate control by temporal redundancy modulation of transcription factor paralogs.

ABSTRACT: Recent single-cell studies have revealed that yeast stress response involves transcription factors that are activated in pulses. However, it remains unclear whether and how these dynamic transcription factors temporally interact to regulate stress survival. Here we show that budding yeast cells can exploit the temporal relationship between paralogous general stress regulators, Msn2 and Msn4, during stress response. We find that individual pulses of Msn2 and Msn4 are largely redundant, and cells can enhance the expression of their shared targets by increasing their temporal divergence. Thus, functional redundancy between these two paralogs is modulated in a dynamic manner to confer fitness advantages for yeast cells, which might feed back to promote the preservation of their redundancy. This evolutionary implication is supported by evidence from Msn2/Msn4 orthologs and analyses of other transcription factor paralogs. Together, we show a cell fate control mechanism through temporal redundancy modulation in yeast, which may represent an evolutionarily important strategy for maintaining functional redundancy between gene duplicates.

SUBMITTER: Wu Y

PROVIDER: S-EPMC8149833 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Current technologies for understanding the transcriptional reprogramming in cells include the transcription factor (TF) chromatin immunoprecipitation (ChIP) experiments and the TF knockout experiments. The ChIP experiments show the binding targets of TFs against which the antibody directs while the knockout techniques find the regulatory gene targets of the knocked-out TFs. However, it was shown that these two complementary results contain few common targets. Researchers have used the concept of TF functional redundancy to explain the low overlap between these two techniques. But the detailed molecular mechanisms behind TF functional redundancy remain unknown. Without knowing the possible molecular mechanisms, it is hard for biologists to fully unravel the cause of TF functional redundancy. RESULTS:To mine out the molecular mechanisms, a novel algorithm to extract TF regulatory modules that help explain the observed TF functional redundancy effect was devised and proposed in this research. The method first searched for candidate TF sets from the TF binding data. Then based on these candidate sets the method utilized the modified Steiner Tree construction algorithm to construct the possible TF regulatory modules from protein-protein interaction data and finally filtered out the noise-induced results by using confidence tests. The mined-out regulatory modules were shown to correlate to the concept of functional redundancy and provided testable hypotheses of the molecular mechanisms behind functional redundancy. And the biological significance of the mined-out results was demonstrated in three different biological aspects: ontology enrichment, protein interaction prevalence and expression coherence. About 23.5% of the mined-out TF regulatory modules were literature-verified. Finally, the biological applicability of the proposed method was shown in one detailed example of a verified TF regulatory module for pheromone response and filamentous growth in yeast. CONCLUSION:In this research, a novel method that mined out the potential TF regulatory modules which elucidate the functional redundancy observed among TFs is proposed. The extracted TF regulatory modules not only correlate the molecular mechanisms to the observed functional redundancy among TFs, but also show biological significance in inferring TF functional binding target genes. The results provide testable hypotheses for biologists to further design subsequent research and experiments.

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Yeast cell fate control by temporal redundancy modulation of transcription factor paralogs.

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