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Mechanisms of epigenetic inheritance by short RNAs

Periodic Reporting for period 4 - RNAEPIGEN (Mechanisms of epigenetic inheritance by short RNAs)

Reporting period: 2020-08-01 to 2021-07-31

Epigenetic mechanisms are considered to be central to the development of multicellular organisms made
of different cell types, all having identical genomes. Similarly, they may explain how genetically identical
organisms are capable of adapting to distinct environmental conditions. Yet, the molecular mechanisms
regulating how epigenetic traits can be inherited during cell division or across generations are not fully
understood. Using the nematode Caenorhabditis elegans, we have recently revealed how the nuclear
Argonaute protein CSR-1 and its associated short RNAs participate in global transcriptional regulation
and chromatin organization. This unprecedented observation opened up a new class of molecular
mechanisms by which Argonaute proteins and their bound short RNAs may actively contribute to epigenetic
inheritance in animals.
This research proposal focuses on the characterization of short-RNA-based mechanisms of epigenetic
inheritance during animal development and upon environmental changes. Using C. elegans as an animal
model system, we plan to integrate genetic, biochemical, and molecular biology tools with high-
throughput genomic and proteomic approaches to dissect (i) the molecular mechanism by which CSR-1-
bound short RNAs regulate transcription, (ii) test their ability in propagating the memory of actively
transcribed genomic regions during early embryonic development, and (iii) characterize their role in
propagating the memory of stress responses across generations to facilitate the adaptation of animals to
environmental changes.
Given the association of nuclear Argonaute proteins with transcriptionally active loci in metazoans, we
anticipate that similar CSR-1-like epigenetic functions are also conserved in humans. Therefore, our research
has the potential to significantly advance our understanding of the molecular mechanisms underlying
epigenetic inheritance and reveals their impact on animal development and adaptation to changing environment.
We are dissecting the mechanism by which nuclear Argonaute proteins regulate transcriptional programs during germline development and we achieved to identify an interesting connection between Argonaute proteins that promote transcription and Argonaute proteins that act as repressors. We are also characterizing how small RNAs regulate embryonic development and zygotic transcription. Finally, we have identified a novel function of a class of small RNAs, called piRNAs, in regulating endogenous transcriptional programs essential for gamete differentiation and functions.
We have identified new potential mechanisms of Argonaute-mediated post-transcriptional regulation of mRNAs delivered to oocytes. Also, we identified the role of piRNAs in promoting transgenerational fertility in isogenic population of worms and in regulating endogenous transcriptional programs essential for animal fertility.