What lies behind the peaceful union between genes and retrotransposons
Present in our genome since the dawn of time, retrotransposons are kept under check, but sometimes they cause pathologies such as cancer, infertility or neurogenerative diseases. How do our cells prevent them from awakening? The “Epigenetic decisions and reproduction” team at Institut Curie (Inserm, CNRS), led by Deborah Bourc’his, reveals a new silencing mechanism in the on-line journal Nature on January 13, 2021, providing perspective on the many ways by which retrotransposons can be harmful.
Our genome contains some 20,000 genes, or 2% of the total DNA mass. By contrast, our DNA contains mostly retrotransposons, present in millions of copies. Retrotransposons are mobile genetic entities, able to move and “jump” in the genome. Among these sequences are found endogenous retroviruses (see box below).
Sometimes beneficial, sometimes pathological: ambiguous relations
Retrotransposons can provide benefits during evolution (for example by creating new genes or new regulatory sequences). However, in the short term, retrotransposons represent a threat through their ability to mutagenize genes upon their mobilization, to modify gene expression or to promote chromosome rearrangements. Accordingly, they are involved in multiple pathological situations, such as infertility, cancer and neurodegenerative diseases. “It is crucial to prevent retrotransposons from jumping and disrupting expression of neighboring genes or the architecture of the genome. Cell are endowed with several defense strategies to targets retrotransposons at all stages of their life cycle”, explains Deborah Bourc’his, Research Director at Inserm and Head of the “Epigenetic decisions and reproduction” team at Institut Curie.
First lines of defense in the cell
Retrotransposons are indeed subject to close cellular monitoring. A first line of defense involves blocking their expression, by DNA methylation for example, a mechanism that Deborah Bourc’his’ team has been broadly studying. But this system sometimes fails: retrotransposons then produce RNAs that the cell has to neutralize, to prevent them from triggering inflammatory responses, with potential pathological consequences.
Through the development of a genetic screen, her team at the Institut Curie demonstrated that cells can biochemically mark retrotransposon RNAs (by m6A methylation), to direct their destabilization and elimination.
“The role of the m6A methylation on the regulation of genic RNAs was well known, and many deregulations of this pathway are found in cancers. But this is the first time that we demonstrate the involvement of m6A methylation in the repression of retrotransposon RNAs, which are themselves a source of instability for the genome”, continues Deborah Bourc’his. This work offers the unique perspective that methylation defects in retrotransposon RNAs may contribute to pathologies such as cancer, and auto-immune and neurodegenerative diseases.
Diagram showing the model for m6A RNA methylation of retrotransposons and its role in the sequestration and deterioration of these RNAs.
In this study, Deborah Bourc’his’ team looked at a specific category of retrotransposons, namely endogenous retroviruses. These sequences are relics of old retroviral infections that have become permanent residents of our genetic material.
m6A RNA methylation regulates the fate of endogenous retroviruses. Tomasz Chelmicki, Emeline Roger, Aurélie Teissandier, Mathilde Dura, Lorraine Bonneville, Sofia Rucli, François Dossin, Camille Fouassier, Sonia Lameiras, Deborah Bourc’his.
Nature, 13 janvier 2021. doi: https://rdcu.be/cdvDM