Post‐Transcriptional Noise Control

Abstract

Recent evidence indicates that transcriptional bursts are intrinsically amplified by messenger RNA cytoplasmic processing to generate large stochastic fluctuations in protein levels. These fluctuations can be exploited by cells to enable probabilistic bet-hedging decisions. But large fluctuations in gene expression can also destabilize cell-fate commitment. Thus, it is unclear if cells temporally switch from high to low noise, and what mechanisms enable this switch. Here, the discovery of a post-transcriptional mechanism that attenuates noise in HIV is reviewed. Early in its life cycle, HIV amplifies transcriptional fluctuations to probabilistically select alternate fates, whereas at late times, HIV utilizes a post-transcriptional feedback mechanism to commit to a specific fate. Reanalyzing various reported post-transcriptional negative feedback architectures reveals that they attenuate noise more efficiently than classic transcriptional autorepression, leading to the derivation of an assay to detect posttranscriptional motifs. It is hypothesized that coupling transcriptional and posttranscriptional autoregulation enables efficient temporal noise control to benefit developmental bet-hedging decisions.

Cell-to-Cell Heterogeneity in Trypanosomes

“…Fluctuations in transcription levels can be either amplified or averaged out posttranscriptionally (59): Amplification is achieved by efficient translation, whereas slow nuclear export (4) or low translation efficiency of mRNA (87) averages out the transcriptional fluctuations by creating a buffering transcript reservoir. Reducing noise can stabilize a certain cellular phenotype, whereas enhanced noise allows for an increase in phenotypic heterogeneity (59). A prominent example for actively controlled transcriptional noise is found during an HIV infection: In early infection stages, the viral TAT protein induces increased transcriptional noise so that the host cells undergo a probabilistic cell fate decision.…”

“…HIV induces a binary fate decision such that cells either actively replicate or become latent. Later in infection, both established cell states are stabilized by the viral REV protein, which reduces transcriptional noise and thereby stabilizes the existing phenotypes (59).…”

RNase E and HupB dynamics foster mycobacterial cell homeostasis and fitness

“…Both intrinsic and extrinsic sources of noise influence the cell biochemical reactions, contributing to the dynamics and magnitude of gene-expression variation and to its attenuation ( Shis et al., 2018 ; McAdams and Arkin, 1997 ; Mitchell and Hoffmann, 2018 ; Patange et al., 2018 ; Megaridis et al., 2018 ; Dame et al, 2020 ; Kim et al., 2020 ). Although all stages of gene expression are subject to variation, low transcript levels translated at a high rate are usually associated with enhanced variation, compared to high transcript levels translated at a low rate ( McAdams and Arkin, 1997 ; Swain, 2004 ; Arbel-Goren et al., 2014 ; Hansen and Weinberger, 2019 ). In other words, the contribution of mRNA turnover to variation is considered to dominate that of proteins, primarily for a difference in their stability.…”

“…Bacterial mRNA half-life is of the order of min at steady state, shorter than the growth-dependent dilution rate; conversely, proteins’ half-life is longer and dominated by dilution. Furthermore, the overall lack of correlation between mRNA and proteins points to the relevance of post-transcriptional regulation and RNA stability in gene expression variation ( Swain, 2004 ; Hansen and Weinberger, 2019 ; Taniguchi et al., 2010 ; Arbel-Goren et al., 2016 ).…”

Different Patterns of mRNA Nuclear Retention during Meiotic Prophase in Larch Microsporocytes

“…This prevents transcriptional chaos and significant fluctuations in the level of proteins in the cytoplasm. It was examined that post-transcriptional and translational auto-regulatory motifs are more effective at noise silencing than common negative-feedback [10]. The role of mRNAs retention in the cell nucleus in the process of post-transcriptional reduction of transcriptional noise was discovered in the last decade and is now extensively studied.…”