Abstract
Transcription is an episodic process characterized by probabilistic bursts; but how these bursts are modulated by cellular physiology remains unclear and has implications for how selection may act on these fluctuations. Using simulations and single-molecule RNA counting, we examined how cellular processes influence transcriptional fluctuations and cell-to-cell variability (noise). The results show that RNA noise is amplified in the cytoplasm compared to the nucleus in ~85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Surprisingly, measurements show substantial further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation-competent states. The multi-state translation-degradation of mRNA also causes substantial noise amplification in protein levels, ultimately accounting for ~74% of intrinsic protein variability in cell populations. Overall, the results demonstrate how transcriptional bursts are intrinsically amplified by mRNA processing and indicate mechanisms through which noise could act as a substrate for evolutionary selection.
Footnotes
- Abbreviations
- smFISH
- (single-molecule fluorescence in situ hybridization);
- TNF-a
- (Tumor Necrosis Factor alpha);
- UBC
- (ubiquitin C);
- EF-1a
- (elongation factor 1 alpha);
- LTR
- (long terminal repeat);
- Simian virus 40
- (SV40).