Non-genetic variations may contribute to expression noise at the transcript or protein levels, resulting in cell-to-cell heterogeneity within an isogenic population. While cells have developed strategies to reduce noise in some cellular functions, this heterogeneity can also facilitate different levels of regulation and provide evolutionary benefits in fluctuating environments. Although several general characteristics of cellular noise have been revealed, detailed molecular pathways underlying noise regulation remained elusive. Here, we established a dual-fluorescent reporter system in Saccharomyces cerevisiae and performed experimental evolution to search for mutations increasing the protein noise. By analyzing evolved cells using bulk segregant analysis coupled with whole-genome sequencing, we identified the histone deacetylase, Hos2, as a negative noise regulator. hos2 mutants down-regulated multiple ribosomal protein genes, leading to compromised protein translation. It suggests that Hos2 may regulate noise by modulating translation machinery. Consistently, treating cells with translation inhibitors as well as mutations in several Hos2 targets, RPS9A, RPS28B and RPL42A, led to increased noise. Our study provides an effective strategy for identifying noise regulators and also sheds light on how cells regulate non-genetic variation through protein translation.
The Histone Deacetylase Hos2 Regulates Protein Expression Noise by Modulating Protein Translation Machinery