Abstract
Transcriptional adaptation is a recently described phenomenon by which a mutation in one gene leads to the transcriptional modulation of related genes, termed adapting genes. At the molecular level, it has been proposed that the mutant mRNA, rather than the loss of protein function, activates this response. While several examples of transcriptional adaptation have been reported in zebrafish embryos and in mouse cell lines, it is not known whether this phenomenon is observed across metazoans. Here we report transcriptional adaptation in C. elegans, and find that this process requires factors involved in mutant mRNA decay, as in zebrafish and mouse. We further uncover a requirement for Argonaute proteins and Dicer, factors involved in small RNA maturation and transport into the nucleus. Altogether, these results provide evidence for transcriptional adaptation in C. elegans, a powerful model to further investigate underlying molecular mechanisms.
Highlights
Transcriptional adaptation is the ability of certain mutations in a gene to modulate the expression of related genes, referred to as adapting genes (El-Brolosy and Stainier, 2017; El-Brolosy et al, 2019; Ma et al, 2019)
Transcriptome analyses suggest that even genes with limited sequence similarity with the mutant mRNA can be upregulated during transcriptional adaptation (ElBrolosy et al, 2019), clearly more work is required to determine whether the upregulation of these genes is a direct or indirect effect of transcriptional adaptation
We found significantly reduced act-5 mRNA levels in act-5(dt2019) mutants compared to wild type (Figure 1A), likely caused by nonsense-mediated decay (NMD) due to a premature termination codon in the first exon (Figure 1A, Figure 1—figure supplement 1)
Summary
Transcriptional adaptation is the ability of certain mutations in a gene to modulate the expression of related genes, referred to as adapting genes (El-Brolosy and Stainier, 2017; El-Brolosy et al, 2019; Ma et al, 2019). According to one model (ElBrolosy et al, 2019), the mutant mRNA, via its degradation products, modulates the expression of adapting genes via transcriptional regulators including antisense RNAs and histone modifiers. The evolutionary importance of related genes that have compensatory effects has been discussed in non-vertebrate eukaryotes (Conant and Wagner, 2004; Plata and Vitkup, 2014) It is not known whether these examples of compensation are due to protein feedback loops or transcriptional adaptation. A few factors are known to be involved in the transcriptional adaptation response far, and others, including some involved in RNA processing and transport, are likely required It is not clear whether the mechanisms of transcriptional adaptation are common or whether each particular case occurs in a different manner, especially at the step leading to transcriptional modulation. We analyze these transcriptional adaptation models after RNAi-mediated knockdown of different genes involved in RNA metabolism and find that the upregulation of the adapting genes requires factors involved in the maturation and transport into the nucleus of small RNAs (sRNAs)
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