Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendents. The histone H3 lysine 4 trimethylation (H3K4me3) complex composed of ASH-2, WDR-5, and the histone methyltransferase SET-2 regulates C. elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5, or SET-2 in the parental generation extend the lifespan of descendents up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendents. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendents.

Protein kinase M ζ (PKMζ) is a constitutively active form of atypical PKC that is exclusively expressed in the brain and implicated in the maintenance of long-term memory1–9. Most studies that support a role for PKMζ in memory maintenance have used pharmacological PKMζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here, we used a genetic approach and targeted exon 9 of the Prkcz gene to generate mice that lack both protein kinase C ζ (PKCζ) and PKMζ (Prkcz−/− mice). Prkcz−/− mice showed normal behavior in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behavior. Surprisingly, they did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference (CPP) for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens (NAc) reduced expression of cocaine CPP in Prkcz−/− mice. In vitro, ZIP and scrambled ZIP inhibited PKMζ, PKCι and PKCζ with similar Ki values. Chelerythrine was a weak inhibitor of PKMζ (Ki = 76 µM). Our findings show that absence of PKMζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKMζ is not present.

It is textbook knowledge that inheritance of traits is governed by genetics, and that the epigenetic modifications an organism acquires are reset between generations. Recently, however, transgenerational epigenetic inheritance has emerged as a rapidly growing field, providing evidence suggesting that some epigenetic changes may result in persistent phenotypes across generations. Here, we survey some of the most recent examples of transgenerational epigenetic inheritance in animals, ranging from C. elegans to humans, and describe approaches and limitations to studying this phenomenon. We also review the current body of evidence implicating chromatin modifications and RNA molecules in mechanisms underlying this unconventional mode of inheritance and discuss its evolutionary implications.

Plants have distinct RNA polymerase complexes (Pol IV and Pol V) with largely unknown roles in maintaining small RNA-associated gene silencing. Curiously, the eudicot Arabidopsis thaliana is not affected when either function is lost. By use of mutation selection and positional cloning, we showed that the largest subunit of the presumed maize Pol IV is involved in paramutation, an inherited epigenetic change facilitated by an interaction between two alleles, as well as normal maize development. Bioinformatics analyses and nuclear run-on transcription assays indicate that Pol IV does not engage in the efficient RNA synthesis typical of the three major eukaryotic DNA-dependent RNA polymerases. These results indicate that Pol IV employs abnormal RNA polymerase activities to achieve genome-wide silencing and that its absence affects both maize development and heritable epigenetic changes.