Dissecting the molecular mechanisms of transgenerational epigenetic inheritance

Small RNAs have a remarkable regulatory role in most eukaryotes.

These molecules bind to Argonaute proteins (AGO) and form a complex that recognizes its mRNA targets by sequence complementarity. The regulatory role is driven by the catalytic activity of AGO, but not exclusively. In several organisms, AGO recruits other factors to perform the silencing.

Remarkably, during transcriptional gene silencing, the small RNA-AGO complex engages factors that interfere with transcription but also proteins that modify the DNA and the chromatin at the targeted loci. This phenomenon has been observed in plants, yeast, flies, and worms.

Particularly, in the nematode Caenorhabditis elegans, this silencing regulation can be triggered and inherited by the next generations.

This reveals the importance of small RNAs and chromatin modifications for transmitting non-genetic information and maintaining germline stability across generations.Several factors required for epigenetic inheritance have been identified by genetic screens in the worms. The nuclear Argonaute, HRDE-1, is expressed in the gonad and is a key component of this pathway.

Still, what are the HRDE-1-associated factors required for transgenerational transcriptional silencing are not fully understood.

This proposal aims to address what are the factors participating in the different stages of silencing mediated by HRDE-1: establishment, inheritance, and maintenance.

To answer these questions, I will employ strains that allow the inducible depletion of the factors involved in the silencing response.

I will combine these tools with encompassing genomics and proteomic approaches to investigate the changes across generations. This proposal will unveil the molecular mechanisms of transgenerational epigenetic inheritance.

Moreover, this study will be instrumental for the study of these responses in other organisms, especially other nematodes, with potential applications to health and ecology.