Régulation de l’expression des séquences répétées et interférence par l’ARN RNA interference, regulation of the expression of repeated sequences and timing of development

Résumé

La défense des organismes contre l’invasion de leur génome par des éléments transposables, des séquences rétrovirales ou des séquences répétées, est essentielle pour le maintien de l’intégrité de l’information génétique. Les mécanismes assurant cette défense restent largement inconnus, mais des résultats récents montrent qu’ils concernent le contrôle de l’expression de ces séquences à la fois au niveau transcriptionnel et post-transcriptionnel. Le contrôle post-transcriptionnel des séquences répétées présente des similitudes avec l’interférence par l’ARN (ARNi), un phénomène spécifique d’extinction des gènes induit par la présence de molécules d’ARN double brin. Ce phénomène est maintenant largement étudié et les différentes étapes de son mécanisme sont progressivement identifiées. Il est particulièrement intéressant de souligner que des acteurs importants du mécanisme de l’ARNi sont également impliqués dans la régulation spatio-temporelle du développement.

Summary

Living organisms have to fight against the invasion of many parasites. Among them are viruses and transposable elements that are able to integrate in the genome of their host. After integration, they can replicate and propagate. The defence mechanisms against these invaders are still largely unknown but are widely studied in plants as well as in fungi and animals, particularly Caenorhabditis elegans and Drosophila melanogaster. The compilation of recent data allows us to draw a general scheme for these mechanisms. In particular, it seems that the propagation of viruses, transposable elements and repeated sequences is controlled by mechanisms repressing the expression of these sequences at both transcriptional and post-transcriptional levels. Post-transcriptional regulation of repeated sequences and transposable elements is related to RNA interference (RNAi), an evolutionary conserved silencing process induced by the presence of double-stranded RNAs (dsRNAs). Many genes and molecular intermediates have now been identified, revealing the different steps of the mechanism underlying this process. Finally, different results suggest that these post-transcriptional silencing processes are involved in the development of organisms. DICER is a nuclease responsible for the processing of dsRNA into short RNA molecules (siRNAs) considered as the interfering agent. siRNAs interact with the transcript of the targeted gene and this interaction induces degradation of the transcript. DICER is also involved in the processing of small temporal RNAs (stRNA) involved in the timing of development. stRNAs have the same structure as siRNAs. They regulate their target genes by interacting with elements present in their 3’UTR and blocking translation. RNAi appears to be an universal regulatory mechanism that was still unknown a few years ago. It is now largely used in large scale inactivation of genes to determine their function, and some recent studies indicate that it might be used in human therapy.