Highlights d Putative histone methyltransferases SET-25 and SET-32 establish heritable silencing d SET-25 and SET-32 are dispensable for silencing maintenance in subsequent generations d Secondary siRNA abundance does not correlate with silencing phenotypes d set-32 and set-25 mutants exhibit aberrant H3K9me3, fertility, and lifespan

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

It is now clear that heredity is not determined purely by Mendelian genetic inheritance; sometimes, epigenetic signals can be passed from parent to progeny for multiple generations. This phenomenon is termed transgenerational epigenetic inheritance (TEI), and examples have now been observed in multiple organisms including plants, flies, mice, and nematodes. Here we discuss the recent findings that TEI is a multi-step process and that the putative chromatin modifiers SET-25 and SET-32 are important in the establishment but not maintenance of silencing.

Summary 13Some epigenetic modifications are inherited from one generation to the next, providing a potential 14 mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of 15 RNA interference phenotypes in Caenorhabditis elegans provides an excellent model to study this 16 phenomenon, and whilst studies have implicated both chromatin modifications and small RNA 17 pathways in heritable silencing their relative contributions remain unclear. Here we demonstrate 18 that the histone methyltransferases SET-25 and SET-32 are required for the establishment of a 19 transgenerational silencing signal but not for long-term maintenance of this signal between 20 subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step 21 process with distinct genetic requirements for establishment and maintenance of heritable silencing. 22Furthermore, small RNA sequencing reveals that the abundance of secondary siRNAs (thought to be 23 the effector molecules of heritable silencing) does not correlate with silencing phenotypes. 24Together, our results suggest that the current mechanistic models of epigenetic inheritance are 25 incomplete. 26

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