Hypoxia induces transgenerational epigenetic inheritance of small RNAs

• Published in: Cell reports (Cambridge) 2022-12, Vol.41 (11), p.111800-111800, Article 111800
• Main Authors: Wang, Simon Yuan, Kim, Kathleen, O’Brown, Zach Klapholz, Levan, Aileen, Dodson, Anne Elizabeth, Kennedy, Scott G., Chernoff, Chaim, Greer, Eric Lieberman
• Format: Article
• Language: English
• Subjects: Animals; C. elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Epigenesis, Genetic; F44E5.4/5; germ granule; HRDE-1; hypoxia; Hypoxia - genetics; Inheritance Patterns; RNA Interference; RNA, Double-Stranded - genetics; RNA, Small Interfering - genetics; small RNA; transgenerational epigenetic inheritance
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111800

Animals sense and adapt to decreased oxygen availability, but whether and how hypoxia exposure in ancestors can elicit phenotypic consequences in normoxia-reared descendants are unclear. We show that hypoxia educes an intergenerational reduction in lipids and a transgenerational reduction in fertility in the nematode Caenorhabditis elegans. The transmission of these epigenetic phenotypes is dependent on repressive histone-modifying enzymes and the argonaute HRDE-1. Feeding naive C. elegans small RNAs extracted from hypoxia-treated worms is sufficient to induce a fertility defect. Furthermore, the endogenous small interfering RNA F44E5.4/5 is upregulated intergenerationally in response to hypoxia, and soaking naive normoxia-reared C. elegans with F44E5.4/5 double-stranded RNA (dsRNA) is sufficient to induce an intergenerational fertility defect. Finally, we demonstrate that labeled F44E5.4/5 dsRNA is itself transmitted from parents to children. Our results suggest that small RNAs respond to the environment and are sufficient to transmit non-genetic information from parents to their naive children. [Display omitted] •Hypoxia causes intergenerational lipid and transgenerational fertility reductions•Transmission of phenotypes requires repressive histone modifications and argonaute HRDE-1•Small RNAs transmit hypoxia signal to the naive worm descendants•Labeled dsRNA F44E5.4/5 is transmitted to F1 and displays a subcellular localization Wang et al. find that hypoxia induces epigenetic inheritance of reduced lipids and fertility in worms and that this is dependent on small RNAs and repressive chromatin modifications. They show that small RNAs are sufficient to induce heritable fertility reductions and track a labeled endogenous dsRNA across generations.