Journal Article

Massively integrated coexpression analysis reveals transcriptional regulation, evolution and cellular implications of the yeast noncanonical translatome

Acar, Omer, Rich, April, Carvunis, Anne-Ruxandra

2024

Overview

Background Recent studies uncovered pervasive transcription and translation of thousands of noncanonical open reading frames (nORFs) outside of annotated genes. The contribution of nORFs to cellular phenotypes is difficult to infer using conventional approaches because nORFs tend to be short, of recent de novo origins, and lowly expressed. Here we develop a dedicated coexpression analysis framework that accounts for low expression to investigate the transcriptional regulation, evolution, and potential cellular roles of nORFs in Saccharomyces cerevisiae . Results Our results reveal that nORFs tend to be preferentially coexpressed with genes involved in cellular transport or homeostasis but rarely with genes involved in RNA processing. Mechanistically, we discover that young de novo nORFs located downstream of conserved genes tend to leverage their neighbors’ promoters through transcription readthrough, resulting in high coexpression and high expression levels. Transcriptional piggybacking also influences the coexpression profiles of young de novo nORFs located upstream of genes, but to a lesser extent and without detectable impact on expression levels. Transcriptional piggybacking influences, but does not determine, the transcription profiles of de novo nORFs emerging nearby genes. About 40% of nORFs are not strongly coexpressed with any gene but are transcriptionally regulated nonetheless and tend to form entirely new transcription modules. We offer a web browser interface ( https://carvunislab.csb.pitt.edu/shiny/coexpression/ ) to efficiently query, visualize, and download our coexpression inferences. Conclusions Our results suggest that nORF transcription is highly regulated. Our coexpression dataset serves as an unprecedented resource for unraveling how nORFs integrate into cellular networks, contribute to cellular phenotypes, and evolve.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animal Genetics and Genomics / Bioinformatics / Biomedical and Life Sciences / Cell cycle / Coexpression networks / data collection / Datasets / De novo gene birth / evolution / Evolution, Molecular / Evolutionary Biology / Evolutionary genetics / Gene Expression Regulation, Fungal / Gene regulation / Genes / Genomes / Homeostasis / Human Genetics / Life Sciences / Microbial Genetics and Genomics / Noncanonical ORFs / Open Reading Frames / Peptides / Phenotypes / Physiology / Plant Genetics and Genomics / Protein Biosynthesis / Proteins / Ribonucleic acid / RNA / RNA processing / RNA transport / Saccharomyces cerevisiae / Saccharomyces cerevisiae - genetics / Saccharomyces cerevisiae - metabolism / smORFs / Sparsity / Transcription / transcription (genetics) / Transcription, Genetic / Transcriptional regulation / Translatome / Yeast / yeasts