Project description
Unlocking secrets of mammalian RNAi features
Viral infections in the genome often produce double-stranded RNA (dsRNA) that can be targeted by RNase III Dicer in the RNA interference (RNAi) pathway. While endogenous mammalian RNAi is present, its physiological characteristics and functions are not fully understood. One reason for this is the inefficient processing of dsRNA by the full-length Dicer, which contributes to mammalian RNAi dormancy. To better understand RNAi function in the germline and assess the antiviral activity of RNAi for animal farming and human therapy, the D-FENS project, funded by the European Research Council, will explore the physiological significance of the N-terminal part of Dicer using genetic animal models. This research aims to uncover species-specific features of RNAi and improve our understanding of its common and unique characteristics.
Objective
Viral infection or retrotransposon expansion in the genome often result in production of double-stranded RNA (dsRNA). dsRNA can be intercepted by RNase III Dicer acting in the RNA interference (RNAi) pathway, an ancient eukaryotic defense mechanism. Notably, endogenous mammalian RNAi appears dormant while its common and unique physiological roles remain poorly understood. A factor underlying mammalian RNAi dormancy is inefficient processing of dsRNA by the full-length Dicer. Yet, a simple truncation of Dicer leads to hyperactive RNAi, which is naturally present in mouse oocytes.
The D-FENS project will use genetic animal models to define common, cell-specific and species-specific roles of mammalian RNAi. D-FENS has three complementary and synergizing objectives:
(1) Explore consequences of hyperactive RNAi in vivo. A mouse expressing a truncated Dicer will reveal at the organismal level any negative effect of hyperactive RNAi, the relationship between RNAi and mammalian immune system, and potential of RNAi to suppress viral infections in mammals.
(2) Define common and species-specific features of RNAi in the oocyte. Functional and bioinformatics analyses in mouse, bovine, and hamster oocytes will define rules and exceptions concerning endogenous RNAi roles, including RNAi contribution to maternal mRNA degradation and co-existence with the miRNA pathway.
(3) Uncover relationship between RNAi and piRNA pathways in suppression of retrotransposons. We hypothesize that hyperactive RNAi in mouse oocytes functionally complements the piRNA pathway, a Dicer-independent pathway suppressing retrotransposons in the germline. Using genetic models, we will explore unique and redundant roles of both pathways in the germline.
D-FENS will uncover physiological significance of the N-terminal part of Dicer, fundamentally improve understanding RNAi function in the germline, and provide a critical in vivo assessment of antiviral activity of RNAi with implications for human therapy.
Fields of science
- medical and health sciencesmedical biotechnologygenetic engineering
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsRNA
- natural sciencesbiological scienceszoologymammalogy
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
142 20 Praha 4
Czechia