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Changes in gene expression can affect phenotypes and therefore both its level and stochastic variability are frequently under selection. It has recently been proposed that epistatic interactions influence gene expression evolution: gene pairs where simultaneous knockout is more deleterious than expected should evolve reduced expression noise to avoid concurrent low expression of both proteins. In apparent support, yeast genes with many epistatic partners have low expression variation both among isogenic individuals and between species. However, the specific predictions and basic assumptions of this verbal model remain untested. Using bioinformatics analysis, we first demonstrate that the model’s predictions are unsupported by available large-scale data. Based on quantitative biochemical modeling, we then show that epistasis between expression reductions (epigenetic epistasis) is not expected to …