Deciphering molecular mechanisms underlying transgenerational inheritance of acquired traits

• Applicant: Dr. Merly Vogt, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2015 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280315489

A central aspect of Jean Baptiste de Lamarcks theory of evolution was his hypothesis that an individuals lifetime experiences and adaptations to specific environmental challenges are heritable, thereby providing future generations with evolutionary advantageous characteristics. Although neglected for a long time, recent discoveries of transgenerational inheritance of epigenetic traits have revived Lamarcks theory as an evolutionary phenomenon. The Hobert laboratory could recently demonstrate for the first time that a naturally occurring environmental change is capable of eliciting a heritable endogenous response. They identified a specific class of small RNAs, the endogenous small interfering (endo-si)RNAs, to be associated with molecular and phenotypic variation across generations in C.elegans. However, it remains unknown, how specific environmental cues can trigger such a heritable response, which cell types are involved and how potential adaptations are maintained and remain effective across generations. The research plan proposed here, will utilize technically and conceptually innovative approaches to explore the physiological and mechanistic basis of transgenerational inheritance of acquired traits in C.elegans. In objective 1, I will first expose worms to different kinds of environmental stressors and will then perform an array of complex behavioral tests in their F3 descendants to identify stress-dependent physiological and behavioral adaptations. Moreover, given the critical role of the central nervous system (CNS) in sensing external stimuli and adapting behavior accordingly, I will further delineate the role of neuronal small RNAs in mediating these effects by knocking out Dicer specifically in the CNS in the parental generation. Using the same paradigms of ancestral stress exposure and CNS-specific Dicer-knockouts, in objective 2, I plan to identify neuron type-specific and small RNA-dependent transgenerational changes in gene expression. To do so, I will isolate mRNAs from different neurocircuits, which will then be subjected to next-generation sequencing and bioinformatical analyses. Finally, by performing unbiased forward genetic screens, objective 3 will define novel key players involved in the initiation of the original stress responses, as well as in the maintenance and inheritance of behavioral and molecular adaptations across generations. Overall, these objectives aim to decipher whether different environmental stressors lead to distinct physiological and molecular adaptations, whether small RNAs are critical for their inheritance and ultimately, to identify the underlying cell type-specific molecular mechanisms and signaling pathways involved. Thus, this proposal tackles the question whether adapted behavior indeed contributes to phenotypic variation and disease susceptibility and therefore holds promise to significantly enhance our current understanding of transgenerational inheritance of acquired traits.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Oliver Hobert