Promoter activity buffering reduces the fitness cost of misregulation

O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY\n\nIn BriefSystematic promoter replacement reveals that coding sequences and 3ends of genes play and active role in buffering cells from fitness defects due to misregulation.\n\nHighlightsO_LIThe 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.\nC_LIO_LIA coupled experimental system and mathematical model quantifies the intrinsic ability of genes to buffer or amplify promoter activity.\nC_LIO_LIPromoter activity buffering reduces the effect of misregulation on fitness.\nC_LI\n\nCells 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. 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 3end of genes, 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.