Braun Maya, Shoshani Shachar, Teixeira Joana, Mellul Shtern Anna, Miller Maya, Granot Zvi, Fischer Sylvia E J, Garcia Susana M D A, Tabach Yuval
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00790 Finland.
iScience. 2022 Apr 11;25(5):104246. doi: 10.1016/j.isci.2022.104246. eCollection 2022 May 20.
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 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.
核苷酸重复扩增是40多种神经退行性疾病的一个标志，会导致RNA毒性和多系统症状，且这些症状会随着年龄的增长而恶化。通过一种尚不清楚的机制，如果重复序列是从母亲那里遗传而来，RNA毒性会在婴儿期引发严重的疾病表现。在这里，我们利用携带扩展CUG重复序列的线虫来表明，这种毒性的不对称代际遗传有助于疾病的发病机制。此外，我们表明这种机制依赖于小RNA途径，来自母体重复序列的小RNA会导致后代的转录组变化、运动能力下降和寿命缩短。我们通过干扰受影响的雌雄同体线虫中的RNAi机制，挽救了后代的毒性表型。这指向了一种将母体偏向与RNAi机制联系起来的新机制，并表明有毒RNA会传递给后代，通过代际表观遗传遗传导致疾病表型。
