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The discrete steps of transcriptional rewiring have been proposed to occur neutrally to ensure steady gene expression under stabilizing selection. A conflict‐free switch of a regulon between regulators may require an immediate compensatory evolution to minimize deleterious effects. Here, we perform an evolutionary repair experiment on the Lachancea kluyveri yeast sef1Δ mutant using a suppressor development strategy. Complete loss of SEF1 forces cells to initiate a compensatory process for the pleiotropic defects arising from misexpression of TCA cycle genes. Using different selective conditions, we identify two adaptive loss‐of‐function mutations of IRA1 and AZF1. Subsequent analyses show that Azf1 is a weak transcriptional activator regulated by the Ras1‐PKA pathway. Azf1 loss‐of‐function triggers extensive gene expression changes responsible for compensatory, beneficial, and trade‐off phenotypes. The trade‐offs can be alleviated by higher cell density. Our results not only indicate that secondary transcriptional perturbation provides rapid and adaptive mechanisms potentially stabilizing the initial stage of transcriptional rewiring but also suggest how genetic polymorphisms of pleiotropic mutations could be maintained in the population. Synopsis: Evolutionary repair in sef1Δ mutant cells of the yeast Lachancea kluyveri highlights the rapid adaptive strategies to handle growth defects and to compensate for gene misexpression. Adaptive clones evolve rapidly in populations of sef1Δ cells under different selective conditions.Loss‐of‐function or hypomorphic mutations pervasively hit two genes, IRA1 and AZF1, which are responsible for the adaptive phenotypes.The pleiotropy of loss‐of‐function azf1 mutations has beneficial fitness and compensatory effects under favorable conditions but results in growth trade‐offs when encountering unfavorable conditions.The growth trade‐offs of azf1 genotypes can be alleviated by increasing the cell density in unfavorable conditions. [ABSTRACT FROM AUTHOR]

Monoubiquitination of histone H2B (to H2Bub1) is required for downstream events including histone H3 methylation, transcription, and mRNA export. The mechanisms and players regulating these events have not yet been completely delineated. Here, we show that the conserved Ran‐binding protein Mog1 is required to sustain normal levels of H2Bub1 and H3K4me3 in Saccharomyces cerevisiae. Mog1 is needed for gene body recruitment of Rad6, Bre1, and Rtf1 that are involved in H2B ubiquitination and genetically interacts with these factors. We provide evidence that the absence of MOG1 impacts on cellular processes such as transcription, DNA replication, and mRNA export, which are linked to H2Bub1. Importantly, the mRNA export defect in mog1Δ strains is exacerbated by the absence of factors that decrease H2Bub1 levels. Consistent with a role in sustaining H2Bub and H3K4me3 levels, Mog1 co‐precipitates with components that participate in these modifications such as Bre1, Rtf1, and the COMPASS‐associated factors Shg1 and Sdc1. These results reveal a novel role for Mog1 in H2B ubiquitination, transcription, and mRNA biogenesis. Synopsis: The conserved Mog1 protein is important for H2Bub1, H3K4me3, transcription, and mRNA export. This novel role is distinct from its known ability to bind Ran‐GTP during protein transport. Mog1 is required to sustain normal levels of H2Bub1 and H3K4me3 and co‐precipitates with components that participate in these modifications in Saccharomyces cerevisiae.The absence of MOG1 impacts on cellular processes linked to H2Bub1, such as transcription and mRNA export.Mog1 binding to Ran is not required for its role in epigenetic modifications. The conserved Mog1 protein is important for H2Bub1, H3K4me3, transcription, and mRNA export. This novel role is distinct from its known ability to bind Ran‐GTP during protein transport. [ABSTRACT FROM AUTHOR]