A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X

Abstract

The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring dynamics of mRNA abundance and translation following DDX3X depletion, we observe stabilization of translationally suppressed mRNAs. We use interpretable statistical learning models to uncover GC content in the coding sequence as the major feature underlying RNA stabilization. This result corroborates GC content-related mRNA regulation detectable in other studies, including hundreds of ENCODE datasets and recent work focusing on mRNA dynamics in the cell cycle. We provide further evidence for mRNA stabilization by detailed analysis of RNA-seq profiles in hundreds of samples, including a Ddx3x conditional knockout mouse model exhibiting cell cycle and neurogenesis defects. Our study identifies a ubiquitous feature underlying mRNA regulation and highlights the importance of quantifying multiple steps of the gene expression cascade, where RNA abundance and protein production are often uncoupled.

mRNA nuclear export: how mRNA identity features distinguish functional RNAs from junk transcripts

“…When synonymous human codons are compared, common codons tend to be GC-rich, and thus may be associated with higher rates of translation elongation [ 111 ]. GC-rich ORFs also protect mRNAs against cytoplasmic decay [ 53 , 111 , 112 ]. Despite all these findings, it has been found that selection between codons for translation optimality in humans is weak and the codon distribution in human protein-coding genes is mostly mediated by non-adaptive evolutionary processes, such as GC-biased gene conversion, which elevates local GC-content [ 113 ].…”