PECA: A Novel Statistical Tool for Deconvoluting Time-Dependent Gene Expression Regulation

Protein
expression varies as a result of intricate regulation of
synthesis and degradation of messenger RNAs (mRNA) and proteins. Studies
of dynamic regulation typically rely on time-course data sets of mRNA
and protein expression, yet there are no statistical methods that
integrate these multiomics data and deconvolute individual regulatory
processes of gene expression control underlying the observed concentration
changes. To address this challenge, we developed Protein Expression
Control Analysis (PECA), a method to quantitatively dissect protein
expression variation into the contributions of mRNA synthesis/degradation
and protein synthesis/degradation, termed RNA-level and protein-level
regulation respectively. PECA computes the rate ratios of synthesis
versus degradation as the statistical summary of expression control
during a given time interval at each molecular level and computes
the probability that the rate ratio changed between adjacent time
intervals, indicating regulation change at the time point. Along with
the associated false-discovery rates, PECA gives the complete description
of dynamic expression control, that is, which proteins were up- or
down-regulated at each molecular level and each time point. Using
PECA, we analyzed two yeast data sets monitoring the cellular response
to hyperosmotic and oxidative stress. The rate ratio profiles reported
by PECA highlighted a large magnitude of RNA-level up-regulation of
stress response genes in the early response and concordant protein-level
regulation with time delay. However, the contributions of RNA- and
protein-level regulation and their temporal patterns were different
between the two data sets. We also observed several cases where protein-level
regulation counterbalanced transcriptomic changes in the early stress
response to maintain the stability of protein concentrations, suggesting
that proteostasis is a proteome-wide phenomenon mediated by post-transcriptional
regulation.