Environmental perturbations lead to extensive directional shifts in RNA processing

Area of Science:

• Molecular Biology
• Genomics
• Environmental Science

Background:

• Environmental factors influence organismal and cellular traits, including gene expression.
• The impact of the environment on RNA processing and alternative splicing is not well understood.
• Genetic variants affecting RNA processing are linked to complex traits, but their environmental context is unclear.

Purpose of the Study:

• To comprehensively characterize environmental effects on RNA processing events across diverse human cell types and conditions.
• To identify specific mechanisms by which environmental perturbations regulate RNA processing.
• To investigate the role of trans factors in mediating environmental responses in RNA processing.

Main Methods:

• Analysis of RNA processing events across 89 environments in five human cell types.
• Identification and classification of RNA processing event shifts.
• Investigation of splicing factor and transcription factor binding in response to environmental stimuli.
• Validation using ATAC-seq and quantitative trait loci (QTL) mapping.

Main Results:

• Over 15,300 RNA processing event shifts were identified in over 4,000 genes across 89 environments.
• Many environmental-induced changes in RNA processing occurred consistently, suggesting global regulation by trans factors.
• Environmental modulation of splicing factor binding predicted intron retention shifts, while transcription factor binding predicted alternative first exon (AFE) usage shifts.
• Specific transcription factors, including ELF2, were identified as key regulators of AFE shifts in response to environmental treatments.

Conclusions:

• Environmental perturbations significantly alter RNA processing through specific, trans factor-regulated mechanisms.
• RNA processing is a dynamic cellular response to environmental changes, impacting gene function and organismal traits.
• Understanding these environmental effects on RNA processing is crucial for comprehending complex traits and disease.