Crosstalk between codon optimality and cis-regulatory elements dictates mRNA stability

Abstract

Background The regulation of messenger RNA (mRNA) stability has a profound impact on gene expression dynamics during embryogenesis. For example, in animals, maternally deposited mRNAs are degraded after fertilization to enable new developmental trajectories. Regulatory sequences in 3′ untranslated regions (3′UTRs) have long been considered the central determinants of mRNA stability. However, recent work indicates that the coding sequence also possesses regulatory information. Specifically, translation in cis impacts mRNA stability in a codon-dependent manner. However, the strength of this mechanism during embryogenesis, as well as its relationship with other known regulatory elements, such as microRNA, remains unclear. Results Here, we show that codon composition is a major predictor of mRNA stability in the early embryo. We show that this mechanism works in combination with other cis-regulatory elements to dictate mRNA stability in zebrafish and Xenopus embryos as well as in mouse and human cells. Furthermore, we show that microRNA targeting efficacy can be affected by substantial enrichment of optimal (stabilizing) or non-optimal (destabilizing) codons. Lastly, we find that one microRNA, miR-430, antagonizes the stabilizing effect of optimal codons during early embryogenesis in zebrafish. Conclusions By integrating the contributions of different regulatory mechanisms, our work provides a framework for understanding how combinatorial control of mRNA stability shapes the gene expression landscape.

Comprehensive Analysis of the Transcriptome-Wide m6A Methylome of Heart via MeRIP After Birth: Day 0 vs. Day 7

“…Besides, FTO has also been found to play a crucial role in the early development of the human central nervous system, and cardiovascular system (28). In recent years, most studies showed there are interactions between miRNAs with m6A in the regulation of messenger RNA (mRNA) stability (29). Even the regulation between themselves is present in several studies (30,31).…”

Transient ribosome slowdown at the decoding step triggers mRNA degradation independent of Znf598 in zebrafish

“…These analyses took advantage of averaging codon effects in multiple different positions on the transcriptome. However, the correlation tended to be modest in part due to the presence of factors that affect mRNA stability independent of codons (e.g., RNA-binding proteins and microRNAs) (Medina-Muñoz et al, 2021). The ORFome approach minimizes this disadvantage by fixing the 5´ and 3´ UTR sequences, yet it also depends on a correlation study, and its target is limited to endogenous mRNA sequences that are under evolutionary constraints (Bazzini et al, 2016;Narula et al, 2019;Wu et al, 2019).…”

iCodon: ideal codon design for customized gene expression

“…Recent studies have revealed that translation strongly affects mRNA stability in cis in a codon-dependent manner in vertebrates (Bazzini et al, 2016;Mishima & Tomari, 2016; as well as in other species (Boël et al, 2016;Burow et al, 2018;de Freitas Nascimento et al, 2018;Harigaya & Parker, 2016;Jeacock, Faria, & Horn, 2018;Presnyak et al, 2015;Radhakrishnan et al, 2016), a process referred as codon optimality (Presnyak et al, 2015). Codon optimality is the most pervasive mechanism underlying mRNA stability in yeast (Cheng, Maier, Avsec, Rus, & Gagneur, 2017) and vertebrates (Medina-Muñoz et al, 2021). Specifically, to determine the regulatory strength of codon optimality in vertebrates, we have recently developed a machine learning model that predicts mRNA stability based on codon composition (Medina-Muñoz et al, 2021).…”

“…Codon optimality is the most pervasive mechanism underlying mRNA stability in yeast (Cheng, Maier, Avsec, Rus, & Gagneur, 2017) and vertebrates (Medina-Muñoz et al, 2021). Specifically, to determine the regulatory strength of codon optimality in vertebrates, we have recently developed a machine learning model that predicts mRNA stability based on codon composition (Medina-Muñoz et al, 2021). Trained with multiple profiles of mRNA stability for thousands of genes obtained from human (Q.…”

“…Trained with multiple profiles of mRNA stability for thousands of genes obtained from human (Q. Wu et al, 2019) and mouse cells (Herzog et al, 2017), as well as Xenopus and zebrafish embryos (Bazzini et al, 2016;Medina-Muñoz et al, 2021), this model has revealed that codon composition is a major determinant of mRNA stability during early embryogenesis and dictates mRNA levels in conjunction with other cis-regulatory elements (e.g., microRNA and m 6 A) in human and mouse cells as well as in zebrafish and Xenopus embryos (Medina-Muñoz et al, 2021). Therefore, we hypothesized that the model could be used as a tool for the design of synonymous coding sequences with differing stability characteristics depending on the desired application.…”