Periodic Reporting for period 4 - RNAflashbacks (The Neuronal Code of Inheritance)
Reporting period: 2024-02-01 to 2025-07-31
This project explored the mechanisms and implications of non-DNA-mediated transgenerational inheritance, focusing on how experiences and molecular responses in the nervous system can influence future generations. The mechanism which enables this in C. elegans nematode, the model system in which transgenerational epigenetic inheritance is best understood, is “small RNA inheritance”. Our discoveries, made owing to this ERC consolidator grant, challenged the traditional view that heredity is exclusively determined by DNA sequence, showing that heritable information can also be conveyed through small RNAs and other molecular carriers, and importantly, we showed that this process can be controlled by the worm’s brain. We uncovered neuronal pathways capable of generating and transmitting small RNA signals that affect gene expression in the germline and in descendants. We identified specific neuronal small RNAs and molecular components responsible for this communication and mapped how environmental stimuli experienced by the parents alter these pathways to produce adaptive effects in their progeny. We also showed that brain-controlled small RNA inheritance is important for adaptation. The project also developed experimental methods to monitor, modulate, and selectively eliminate heritable small RNA effects, creating a framework for future investigations into how epigenetic inheritance shapes evolution, development, and physiological adaptation.
Throughout the project we investigated how neuronal activity can influence germline gene regulation and induce transgenerational inheritance in Caenorhabditis elegans. We identified specific neuronal small RNAs and signaling pathways that communicate environmental information to the germline, leading to heritable changes in gene expression and offspring physiology. Using genetic, molecular, and imaging approaches, we demonstrated that neuronal stimuli can trigger small RNA production and transport to non-neuronal tissues, establishing a mechanistic link between experience and inheritance.
We developed new experimental tools to visualize the effects of and to manipulate heritable small RNA responses, including reporter systems and genetic strains that allow selective activation or removal of neuronal inheritance signals. These tools now enable systematic testing of the principles governing non-DNA-based inheritance and provide a platform for studying similar mechanisms in other species.
The results were disseminated through publications, conference presentations, and outreach activities that engaged both the scientific community and the general public. The findings have generated broad interest in the fields of epigenetics, neurobiology, and evolution, opening new directions for understanding how experience-dependent information can persist across generations and influence adaptation.
To achieve these goals, I assembled a multidisciplinary team combining expertise in biology, physics, and computer science. Together, we demonstrated that small RNAs produced in the nervous system of C. elegans can induce heritable effects that persist for multiple generations. We identified genes whose expression is regulated transgenerationally by neuronal activity in the ancestors and characterized several behavioral traits influenced by the environmental experiences of previous generations. In addition, we discovered both natural and engineered mechanisms capable of resetting heritable small RNA responses, including those originating in neurons, thereby establishing experimental control over the inheritance process.
We developed new experimental tools to visualize the effects of and to manipulate heritable small RNA responses, including reporter systems and genetic strains that allow selective activation or removal of neuronal inheritance signals. These tools now enable systematic testing of the principles governing non-DNA-based inheritance and provide a platform for studying similar mechanisms in other species.
The results were disseminated through publications, conference presentations, and outreach activities that engaged both the scientific community and the general public. The findings have generated broad interest in the fields of epigenetics, neurobiology, and evolution, opening new directions for understanding how experience-dependent information can persist across generations and influence adaptation.
To achieve these goals, I assembled a multidisciplinary team combining expertise in biology, physics, and computer science. Together, we demonstrated that small RNAs produced in the nervous system of C. elegans can induce heritable effects that persist for multiple generations. We identified genes whose expression is regulated transgenerationally by neuronal activity in the ancestors and characterized several behavioral traits influenced by the environmental experiences of previous generations. In addition, we discovered both natural and engineered mechanisms capable of resetting heritable small RNA responses, including those originating in neurons, thereby establishing experimental control over the inheritance process.
The project has advanced well beyond the state of the art, generating published and forthcoming results that redefine the understanding of epigenetic inheritance and how it is controlled by the brain. We discovered that transient, non-genetic brain-controlled responses to environmental conditions can produce heritable effects on behavior that persist across multiple generations. Furthermore, through adaptation and competition experiments, we demonstrated that inherited small RNA responses can alter both phenotypic outcomes and genomic composition. These findings provide direct experimental evidence suggesting that epigenetic inheritance contributes to evolutionary dynamics, extending its relevance from short-term adaptation to long-term evolutionary processes.