Transgenerational epigenetic inheritance

We have previously identified chromatin-modifying enzymes that regulate complex transgenerational phenotypes in C. elegans, including longevity and fertility. Mutation of a histone H3 lysine 4 (H3K4) trimethylation complex regulates worm lifespan in both the generation in which the mutation occurs and in subsequent generations lacking the mutation. More recent work focuses on understanding how deletion of the C. elegans H3K4me2 demethylase, spr-5, leads to inherited accumulation of the euchromatic H3K4me2 mark and a progressive decline in fertility in successive generations. To investigate the underlying molecular mechanism behind progressive sterility of spr-5 mutant worms, we carried out an RNAi screen and identified both suppressors and enhancers of sterility. This screen led to a working model for how epigenetic changes in histone H3 methylation might be inherited to affect complex organismal traits.

Current projects are focused on identifying new paradigms of epigenetic inheritance and characterization of which epigenetic cues are transmitted from ancestors to their descendants to regulate complex biological phenotypes. We have recently performed metabolic methyl labeling experiments to track heritable methylation from parents to their children and found that in response to parental starvation there is an increase in 18S rRNA methylation that is passed to children to alter translation in preparation for less food availability. Parental starvation leads to a hormesis phenotype, where one stress will induce the stress response pathways so that organisms respond better to other stresses. In C. elegans, parental starvation leads to increased heat stress resistance, a subtle increase in lifespan, and a reduction in fertility that is passed on to the children and grandchildren before returning to basal levels in the F3 generation. We find that deletion of the 18S rRNA methyltransferases eliminates the transmission of this transgenerational hormesis phenotypes to the naive well fed descendants.

Preprints

Intergenerational hormesis is regulated by heritable 18S rRNA methylation

September 27, 2021

Liberman N, Gerashchenko M, Boulias K, MacWhinnie F, Ying AK, Taylor AF, Al Haddad J, Shibuya H, Roach L, Dong A, Gladyshev VN, and Greer EL, Intergenerational hormesis is regulated by heritable 18S rRNA methylation bioRxiv doi: https://doi.org/10.1101/2021.09.27.461965 (2021)

Publications