Intergenerational hormesis is regulated by heritable 18S rRNA methylation

Abstract

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labelling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans. We find that methylation is transmitted to descendants in proteins, RNA, DNA and lipids. We further find that in response to parental starvation, fed naive progeny display reduced fertility, increased heat stress resistance, and extended longevity. This intergenerational hormesis is accompanied by a heritable increase in N6-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified the conserved DIMT-1 as the m6,2A methyltransferase in C. elegans and find that dimt-1 is required for the intergenerational hormesis phenotypes. This study provides the first labeling and tracking of heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating the heritable response to starvation.

From correlation to causation: The new frontier of transgenerational epigenetic inheritance

“…Through a series of genetic tricks, histone modifications present in sperm were shown to be passed on to the next generation, affecting the transcriptomic profile and development of the progeny [81,82] . Our own work performing a metabolic methyl labeling technique across generations allowed us to identify, in an unbiased manner, which methylation events were transmitted from parents to their children, in response to parental starvation [66] (Figure 2). These types of approaches shift the focus in the field from correlation to causation, where we can directly track and monitor the passage of epigenetic information from parent to child.…”

“…Our group has found, through metabolic methyl labeling experiments, that in response to starvation there is a heritable increase in m 6,2 A on the 18S rRNA in C. elegans [ 66 ] (Figure 1C). Starvation induces a hormesis response with increased heat resistance and a subtle extension in lifespan associated with a decrease in reproduction, in not only the generation that is starved, but also in their naïve well fed children and grandchildren.…”

“…Starvation induces a hormesis response with increased heat resistance and a subtle extension in lifespan associated with a decrease in reproduction, in not only the generation that is starved, but also in their naïve well fed children and grandchildren. [ 66 ] We identified the enzymes responsible for N6‐dimethylating adenosines on the 18S rRNA in C. elegans , and found that deletion of these enzymes eliminated the transmission of hormesis phenotypes in response to parental starvation. [ 66 ] Based on these findings, it suggests that rRNA become modified in response to external stresses, to presumably alter which proteins are translated to increase survival in stressful conditions.…”

“…[ 66 ] We identified the enzymes responsible for N6‐dimethylating adenosines on the 18S rRNA in C. elegans , and found that deletion of these enzymes eliminated the transmission of hormesis phenotypes in response to parental starvation. [ 66 ] Based on these findings, it suggests that rRNA become modified in response to external stresses, to presumably alter which proteins are translated to increase survival in stressful conditions. These modified rRNAs are then transmitted to the next generation to alert subsequent generations that conditions might not be optimal, and the children should also alter which proteins are translated to prepare for that stressed environment.…”

Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring

“…Then, 100 ng purified RNA samples were digested to nucleosides for 2 hr at 37°C using the Nucleoside Digestion mix (NEB, M069S). Quantifications were performed as in 84 , briefly: digested RNA samples were diluted to 100 μl with ddH20 and filtered through 0.22 μm Millex Syringe Filters. 5 μl of the filtered solution was injected for LC-MS/MS analysis using the Agilent 1290 UHPLC-MS/MS system with a Hypersil Gold C18 reversed-phase column (2.1 x 150 mm, 3 μm).…”