Codon identity regulates mRNA stability and translation efficiency during the maternal‐to‐zygotic transition

Abstract

Cellular transitions require dramatic changes in gene expression that are supported by regulated mRNA decay and new transcription. The maternal-to-zygotic transition is a conserved developmental progression during which thousands of maternal mRNAs are cleared by post-transcriptional mechanisms. Although some maternal mRNAs are targeted for degradation by microRNAs, this pathway does not fully explain mRNA clearance. We investigated how codon identity and translation affect mRNA stability during development and homeostasis. We show that the codon triplet contains translation-dependent regulatory information that influences transcript decay. Codon composition shapes maternal mRNA clearance during the maternal-to-zygotic transition in zebrafish, Xenopus, mouse, and Drosophila, and gene expression during homeostasis across human tissues. Some synonymous codons show consistent stabilizing or destabilizing effects, suggesting that amino acid composition influences mRNA stability. Codon composition affects both polyadenylation status and translation efficiency. Thus, the ribosome interprets two codes within the mRNA: the genetic code which specifies the amino acid sequence and a conserved "codon optimality code" that shapes mRNA stability and translation efficiency across vertebrates.

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

“…One example of this is codon-mediated stability control. Although a causal link from codon usage to mRNA half-life has been shown for a wide range of organisms (Hoekema et al 1987;Presnyak et al 2015;Bazzini et al 2016;Mishima and Tomari 2016), the underlying mechanism remains poorly understood. In S. cerevisiae, reporter gene experiments showed that codon-mediated stability control depends on the RNA helicase Dhh1 .…”

“…For instance, inserting strong secondary structure elements in the 5 ′ UTR or modifying the translation start codon context strongly destabilizes the long-lived PGK1 mRNA in S. cerevisiae (Muhlrad et al 1995;LaGrandeur and Parker 1999). Codon usage, which affects the translation elongation rate, also regulates mRNA stability (Hoekema et al 1987;Presnyak et al 2015;Bazzini et al 2016;Mishima and Tomari 2016). Further correlations between codon usage and mRNA stability have been reported in E. coli and S. pombe (Boël et al 2016;Harigaya and Parker 2016).…”

Dynamic RNA–protein interactions underlie the zebrafish maternal-to-zygotic transition

“…Strong coupling between poly(A) tail length and translation efficiency (TE) has been observed in the cleavage embryos of many species (Subtelny et al 2014;Eichhorn et al 2016;Lim et al 2016), although the molecular mechanisms that enable this coupling remain unclear. Recent studies have begun to determine a variety of mechanisms through which maternal mRNA clearance is accomplished (Giraldez et al 2006;Tadros et al 2007;Lund et al 2009;Tadros and Lipshitz 2009;Barckmann et al 2015;Bazzini et al 2016;Mishima and Tomari 2016). An important role has been ascribed to the evolutionarily conserved miRNA, miR-430/427, that mediates translational repression and clearance of a subset of maternal mRNAs in zebrafish and Xenopus embryos during MZT (Giraldez et al 2006;Lund et al 2009).…”

Codon optimality and mRNA decay

“…Moreover, specific sequence motifs that are recognized by trans-acting factors, such as microRNAs and RNA-binding proteins, often modulate mRNA stability by controlling translation initiation. This inverse relationship between translation initiation and degradation can be rationalized as the cap and poly(A) tail either being in a translationally competent mRNP or in an alternative nuclease accessible complex.Studies in organisms from E. coli to zebrafish now demonstrate that the "optimality" of an mRNA's codons modulates its stability [2][3][4][5]. The general theme is that "optimal" codons, which are recognized by abundant tRNAs and efficiently translated, are correlated with mRNA stability, whereas "non-optimal" codons, which are recognized by less abundant tRNAs, are correlated with mRNA instability.…”

“…Studies in organisms from E. coli to zebrafish now demonstrate that the "optimality" of an mRNA's codons modulates its stability [2][3][4][5]. The general theme is that "optimal" codons, which are recognized by abundant tRNAs and efficiently translated, are correlated with mRNA stability, whereas "non-optimal" codons, which are recognized by less abundant tRNAs, are correlated with mRNA instability.…”