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

Santiago Gerardo Medina-Muñoz,Ariel Alejandro Bazzini,Luciana Andrea Castellano,María José Blanco Salazar,Michay Diez,Michelle Lynn Devore,Gopal Kushawah

doi:10.1186/s13059-020-02251-5

Abstract

BackgroundThe 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.ResultsHere, 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.ConclusionsBy 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.

Highlights

The regulation of messenger RNA stability has a profound impact on gene expression dynamics during embryogenesis
We investigated whether the codon optimality effect on messenger RNA (mRNA) stability can be detected in mRNAs that are regulated by cis-elements during the zebrafish (Table S1; Additional file 1: Fig. S1a-c) and Xenopus
For decades, research on mRNA stability and on mRNA clearance during developmental transitions, has been focused predominantly on cis-regulatory elements that reside outside the coding sequence, mostly within the 3′ untranslated regions (3′UTRs)

Summary

Introduction

The regulation of messenger RNA (mRNA) stability has a profound impact on gene expression dynamics during embryogenesis. MicroRNAs, mRNA modifications, and some RNA binding proteins affect mRNA stability by recognizing regulatory elements mainly in the 3′UTR [3,4,5,6,7] or across the entire mRNA [8,9,10,11,12,13]. These cis-regulatory elements can, in turn, affect how a cell grows, differentiates, and responds to its Medina-Muñoz et al Genome Biology (2021) 22:14 environment [2, 14]. Despite the identification of these and other factors, it is still unclear how most maternal mRNAs are degraded [15]

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Conclusion