Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats
Summary: Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases and cause RNA toxicity and multisystemic symptoms that worsen with age. Through an unclear mechanism, RNA toxicity can trigger severe disease manifestation in infants if the repeats are inherited from their mo...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-05-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222005168 |
| _version_ | 1811339923387580416 |
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| author | Maya Braun Shachar Shoshani Joana Teixeira Anna Mellul Shtern Maya Miller Zvi Granot Sylvia E.J. Fischer Susana M.D. A. Garcia Yuval Tabach |
| author_facet | Maya Braun Shachar Shoshani Joana Teixeira Anna Mellul Shtern Maya Miller Zvi Granot Sylvia E.J. Fischer Susana M.D. A. Garcia Yuval Tabach |
| author_sort | Maya Braun |
| collection | DOAJ |
| description | Summary: Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases and cause RNA toxicity and multisystemic symptoms that worsen with age. Through an unclear mechanism, RNA toxicity can trigger severe disease manifestation in infants if the repeats are inherited from their mother. Here we use Caenorhabditis elegans bearing expanded CUG repeats to show that this asymmetric intergenerational inheritance of toxicity contributes to disease pathogenesis. In addition, we show that this mechanism is dependent on small RNA pathways with maternal repeat-derived small RNAs causing transcriptomic changes in the offspring, reduced motility, and shortened lifespan. We rescued the toxicity phenotypes in the offspring by perturbing the RNAi machinery in the affected hermaphrodites. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring, causing disease phenotypes through intergenerational epigenetic inheritance. |
| first_indexed | 2024-04-13T18:33:38Z |
| format | Article |
| id | doaj.art-d676fb5f1b654b059ca467422dae29ee |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-13T18:33:38Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-d676fb5f1b654b059ca467422dae29ee2022-12-22T02:34:58ZengElsevieriScience2589-00422022-05-01255104246Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeatsMaya Braun0Shachar Shoshani1Joana Teixeira2Anna Mellul Shtern3Maya Miller4Zvi Granot5Sylvia E.J. Fischer6Susana M.D. A. Garcia7Yuval Tabach8Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, IsraelInstitute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00790 FinlandDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, IsraelDivision of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USAInstitute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00790 Finland; Corresponding authorDepartment of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Corresponding authorSummary: Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases and cause RNA toxicity and multisystemic symptoms that worsen with age. Through an unclear mechanism, RNA toxicity can trigger severe disease manifestation in infants if the repeats are inherited from their mother. Here we use Caenorhabditis elegans bearing expanded CUG repeats to show that this asymmetric intergenerational inheritance of toxicity contributes to disease pathogenesis. In addition, we show that this mechanism is dependent on small RNA pathways with maternal repeat-derived small RNAs causing transcriptomic changes in the offspring, reduced motility, and shortened lifespan. We rescued the toxicity phenotypes in the offspring by perturbing the RNAi machinery in the affected hermaphrodites. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring, causing disease phenotypes through intergenerational epigenetic inheritance.http://www.sciencedirect.com/science/article/pii/S2589004222005168Molecular biologyMolecular geneticsDevelopmental biology |
| spellingShingle | Maya Braun Shachar Shoshani Joana Teixeira Anna Mellul Shtern Maya Miller Zvi Granot Sylvia E.J. Fischer Susana M.D. A. Garcia Yuval Tabach Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats iScience Molecular biology Molecular genetics Developmental biology |
| title | Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats |
| title_full | Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats |
| title_fullStr | Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats |
| title_full_unstemmed | Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats |
| title_short | Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats |
| title_sort | asymmetric inheritance of rna toxicity in c elegans expressing ctg repeats |
| topic | Molecular biology Molecular genetics Developmental biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222005168 |
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