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HEIndividual fellowship2023–2025

MOMENTS · Dissecting the molecular mechanisms of transgenerational epigenetic inheritance

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-04-01 → 2025-03-31
EU contribution
€195,915
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

Dissecting the molecular mechanisms of transgenerational epigenetic inheritance

The successful development and survival of organisms in different environments rely on their ability to regulate gene expression in a precise, timely, and coordinated manner. Genes are not continuously active; instead, they must be turned on or off in specific cells and moments. To achieve this, organisms have evolved sophisticated regulatory systems. Among these, Argonaute proteins, present in several domains of life, play a central regulatory role. They bind to small RNAs to recognize specific messenger RNAs (mRNAs) by sequence complementarity and negatively regulate their expression. Beyond their regulatory role in animal development, small RNA-mediated silencing can also be inherited across generations. This phenomenon, known as epigenetic inheritance, allows offspring to "remember" and respond to environmental or developmental experiences of their ancestors. However, not all experiences are passed on, nor do these molecular memories persist indefinitely. This raises fundamental questions: How do organisms decide which molecular memories to retain? How long are they maintained? What mechanisms ensure their inheritance? This project set out to investigate these questions by exploring how nuclear Argonautes and small RNAs can execute their gene silencing and inheritance functions in the germline of Caenorhabditis elegans, a widely used model organism. While the role of nuclear Argonautes in epigenetic inheritance was recognized, the mechanisms remained unclear. This project aimed to: 1) Identify the factors involved in the maintenance of silencing across generations 2) Decipher the molecular mechanisms underlying small RNA-mediated transcriptional repression 3) Clarify how these regulatory systems work during development and over successive generations. By deepening our understanding of heritable gene regulation, this research contributes to the broader field of epigenetics and may ultimately inform areas such as developmental biology and intergenerational health.

Data: CORDIS, © European Union

Project objective

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.

Original text from CORDIS.

Participants

  • INSTITUT PASTEUR · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union