Translational buffering tunes gene expression in mice and humans

Area of Science:

• Molecular Biology
• Genomics
• Systems Biology

Background:

• Translational buffering regulates ribosome occupancy to counteract transcriptional variation.
• Previous studies focused on yeast, leaving its prevalence in mammalian genes unclear.
• Understanding translational buffering in diverse cellular contexts is essential.

Purpose of the Study:

• To investigate the extent and conservation of translational buffering across mammalian genes.
• To identify features and mechanisms underlying translational buffering.
• To assess the role of translational buffering in protein abundance stability and gene dosage sensitivity.

Main Methods:

• Uniform analysis of 1,515 matched ribosome profiling and RNA-seq datasets from humans and mice.
• Comparative analysis of ribosome occupancy and RNA expression variation.
• Examination of the relationship between mRNA abundance and translation efficiency.

Main Results:

• Translational buffering is partially conserved between humans and mice, with shared buffered genes enriched for ribosomal, RNA-binding, and proteasomal proteins.
• Sequence features alone cannot predict translational buffering, emphasizing the role of cellular context.
• Buffered genes exhibit reduced protein abundance variation in cancer and are often haploinsufficient or triplosensitive.

Conclusions:

• Translational buffering is a widespread mechanism in mammals, contributing to protein homeostasis.
• Two models, 'differential accessibility' and 'translation initiation rate', may explain transcript-specific buffering.
• The study provides insights into the features and mechanisms of translational buffering across diverse conditions.