Organisms regulate gene expression through changes in the activity of transcription factors (TFs). In yeast, the response of genes to changes in TF activity is generally assumed to be encoded in the promoter. To directly test this assumption, we chose 42 genes and, for each, replaced the promoter with a synthetic inducible promoter and measured how protein expression changes as a function of TF activity. Most genes exhibited gene-specific TF dose-response curves not due to differences in mRNA stability, translation, or protein stability. Instead, most genes have an intrinsic ability to buffer the effects of promoter activity. This can be encoded in the open reading frame and the 3' end of genes and can be implemented by both autoregulatory feedback and by titration of limiting trans regulators. We show experimentally and computationally that, when misexpression of a gene is deleterious, this buffering insulates cells from fitness defects due to misregulation.
Graphical AbstractIn Brief Systematic promoter replacement reveals that coding sequences and 3'UTRs play and active role in buffering cells from fitness defects due to misregulation. Highlights• The TF dose-response curve --how gene expression changes as a function of TF concentration --is encoded throughout the gene, not only in the promoter. Genes with the same promoter have different TF DRCs.• A coupled experimental system and mathematical model quantifies the intrinsic ability of genes to buffer or amplify promoter activity.• Promoter activity buffering reduces the effect of misregulation on fitness.. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/215186 doi: bioRxiv preprint first posted online Nov. 6, 2017; 2 Promoter activity buffering reduces the fitness cost of misregulation. Author Contributions Conceptualization Writing & figures Data analysis ExperimentsMiquel Àngel Schikora- Tamarit 1 Miquel Àngel Schikora- Tamarit 1 Miquel Àngel Schikora- Tamarit 1 Miquel Àngel Schikora- Tamarit Cells regulate gene expression by changing the concentration and activity of transcription factors (TFs). The response of each gene to changes in TF activity is generally assumed to be encoded in the promoter. Here we show that, even when the promoter itself remains constant, each gene has a unique TF dose response curve. Many genes have an intrinsic ability to either buffer or amplify the effects of high promoter activity. We present a coupled mathematical model and experimental system for quantifying this property. Promoter activity buffering can be encoded by sequences in both the open reading frame and 3'UTR and can be implemented by both autoregulatory feedback loops and by titration of limiting trans regulators. We show experimentally that promoter activity buffering insulates cells from fitness defects due to misexpression. The response of genes to changes in [TF] is encoded by sequences outside of the promoter, and this effect can either insulate or amplify the effects of aneuploidy and misregulation on organismal fitness. INTRODUCTIONUnderstanding how changes in transcription factor activity lead to changes in gene expression is essential for understanding how organisms regulate expression in response to external and internal signals, and for understanding how sequence variation in genomes affects phenotype Levo and Segal, 2014;López-Maury et al., 2008;Segal and Widom, 2009). Changes in gene expression are associated with clinically relevant phenotypes such as disease and differential response to drugs, and the current assumption is that much variation in phenotype and expression is due to sequence variation in classical regulatory regions such as enhancers and promoters (Albert and Kruglyak, 2015). However, current mathematical models of . CC-BY-NC-ND 4.0 International license It is made available unde...
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