Experimental evolution reveals a general role for the methyltransferase Hmt1 in noise buffering

Shu-Ting You; Yu-Ting Jhou; Cheng-Fu Kao; Jun-Yi Leu

doi:10.1371/journal.pbio.3000433

Experimental evolution reveals a general role for the methyltransferase Hmt1 in noise buffering

PLoS Biol. 2019 Oct 15;17(10):e3000433. doi: 10.1371/journal.pbio.3000433. eCollection 2019 Oct.

Authors

Shu-Ting You^{1

2}, Yu-Ting Jhou², Cheng-Fu Kao³, Jun-Yi Leu^{1

2}

Affiliations

¹ Molecular and Cell Biology, Taiwan International Graduate Program, Graduate Institute of Life Sciences, National Defense Medical Center and Academia Sinica, Taipei, Taiwan.
² Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
³ Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.

Abstract

Cell-to-cell heterogeneity within an isogenic population has been observed in prokaryotic and eukaryotic cells. Such heterogeneity often manifests at the level of individual protein abundance and may have evolutionary benefits, especially for organisms in fluctuating environments. Although general features and the origins of cellular noise have been revealed, details of the molecular pathways underlying noise regulation remain elusive. Here, we used experimental evolution of Saccharomyces cerevisiae to select for mutations that increase reporter protein noise. By combining bulk segregant analysis and CRISPR/Cas9-based reconstitution, we identified the methyltransferase Hmt1 as a general regulator of noise buffering. Hmt1 methylation activity is critical for the evolved phenotype, and we also show that two of the Hmt1 methylation targets can suppress noise. Hmt1 functions as an environmental sensor to adjust noise levels in response to environmental cues. Moreover, Hmt1-mediated noise buffering is conserved in an evolutionarily distant yeast species, suggesting broad significance of noise regulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CRISPR-Cas Systems
Directed Molecular Evolution
Ethyl Methanesulfonate / pharmacology
Gene Editing
Gene Expression Regulation, Fungal*
Genes, Reporter
Genetic Heterogeneity*
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / genetics
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Methylation
Mutation
Protein Processing, Post-Translational*
Protein-Arginine N-Methyltransferases / genetics*
Protein-Arginine N-Methyltransferases / metabolism
Repressor Proteins / genetics*
Repressor Proteins / metabolism
Saccharomyces cerevisiae / drug effects
Saccharomyces cerevisiae / genetics*
Saccharomyces cerevisiae / growth & development
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins / genetics*
Saccharomyces cerevisiae Proteins / metabolism

Substances

Repressor Proteins
Saccharomyces cerevisiae Proteins
Green Fluorescent Proteins
Ethyl Methanesulfonate
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
TDH2 protein, S cerevisiae
HMT1 protein, S cerevisiae
Protein-Arginine N-Methyltransferases

Grants and funding

Funding was received from Academia Sinica (https://www.sinica.edu.tw/en; grant number AS-IA-105-L01 and AS-TP-107-ML06; to J-YL) and Taiwan Ministry of Science and Technology (https://www.most.gov.tw/?l=en; grant number 107-2321-B-001-010; to J-YL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.