Editors' ChoiceGenetic Diseases

Transcriptional adaptation: Another reason why your disease model fails you

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Science Translational Medicine  24 Apr 2019:
Vol. 11, Issue 489, eaax1731
DOI: 10.1126/scitranslmed.aax1731

Abstract

Up-regulation of paralogous transcripts is a potential mechanism of genetic compensation.

The career of a researcher is littered with project failures. Perhaps the biggest (and most expensive) failures are those related to the development of new animal models of diseases. There are always little stories whispered about “that animal model” where a genetic knockout failed to produce any obvious phenotype. This little tragedy for a young scientist’s career could be due to genetic robustness, the capacity of genetic networks to adapt to mutations. Several mechanisms have been proposed to comfort the poor PhD or Postdoc who saw their project severely compromised. Among them are functional redundancy and the rewiring of genetic networks to adapt to the lack of a certain factor.

El-Brolosy and colleagues proposed a new mechanism, transcriptional adaptation, as another factor underlying genetic robustness. They found that specific mutations in a given mRNA resulted in faster decay of that mRNA and induced increased transcription of genes in the same transcript family. They named these paralogs “adapting genes”. In zebrafish mutants, transcriptional adaptation required a certain sequence similarity between the adapting genes and the mutated mRNA and was partially dependent on chromatin remodeling. Experiments performed in mouse embryonic stem cells and fibroblasts suggested the existence of a similar mechanism in mammals. The authors’ hypothesis was that transcriptional adaptation relies on the mRNA fragments derived from the degradation of the mutant gene, alone or in combination with decay factors or other RNA binding proteins. These fragments may increase the transcription of the adapting genes by interacting with chromatin remodeling proteins or by reducing the repression due to antisense RNA of the adapting gene.

In conclusion, this paper shows the existence of a new mRNA-dependent mechanism that accounts for the adaptation to nonsense mutations originating aberrant mRNAs. This adaptation may explain also the partial penetrance of some genetic diseases. An understanding of the adaptation mechanisms allows for the identification of potential disease modifiers and the elaboration of new therapeutic strategies and, of course, it may explain why your disease model has failed you.

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