Mounting evidence in several organisms suggests that some epigenetic modifications acquired by an individual during its lifetime can be inherited for multiple future generations. This phenomenon, termed transgenerational epigenetic inheritance, may provide a mechanism for the inheritance of environmentally acquired traits. We are studying transgenerational epigenetic inheritance using a model organism, the nematode Caenorhabditis elegans.
We have developed a system in which RNAi-induced silencing of a GFP transgene is robustly inherited for multiple generations in the absence of the initial RNAi trigger. We show that the histone methyltransferase SET-25 and the putative histone methyltransferase SET-32 are required for effective transmission of transgene silencing. Specifically, whilst set-25 and set-32 mutant animals exposed to RNAi display transgene silencing, their unexposed offspring fail to inherit silencing. Intriguingly, the few animals which escape this failure and remain silenced then produce subsequent generations of silenced progeny. Furthermore, set-25 and set-32 mutants segregated from silenced set-25/+ and set-32/+ heterozygotes respectively remain fully silenced. Together, this data suggests that SET-25 and SET-32 are required for the establishment of a transgenerational silencing signal, but not for long-term maintenance of this signal between subsequent generations. We thus propose a three-step model of transgenerational epigenetic inheritance consisting of Initiation, Establishment and Maintenance. Small RNA sequencing experiments are underway to further test this.
SET-32 is uncharacterised, so we are also investigating its broader functions. We show that set-32 mutant hermaphrodites have reduced fertility, producing fewer live offspring, fewer total eggs and more unfertilised eggs in comparison to wild-type animals. This reduced fertility is rescued by providing mutant hermaphrodites with wild-type sperm, indicating a male germline defect. Closer investigation reveals that set-32 mutant sperm are defective in crawling. Furthermore, set-32 mutant animals display extended lifespan independent of reduced fertility, providing new insight into the little-understood contribution of chromatin modifiers to lifespan regulation.