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. We also identified a novel form of DNA modifications in Metazoa, methylation of adenines (6mA), which may be responsible for stable transgenerational epigenetic inheritance.

Future studies will focus on experimentally testing this working model and 1) identification of the molecules that are inherited to regulate these transgenerational phenotypes, 2) how environmental cues alter an organism’s epigenetic landscape, and 3) determining how an epigenetic mark can be stably maintained or removed. We will address these questions using a combination of genetic, genomic and biochemical approaches in C. elegans and mammalian systems.