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SUMMARYEnvironmental stress-induced epigenetic changes are inherited by germlines and profoundly affect the behavior and physiology of subsequent generations. However, the mechanisms by which acquired transgenerational epigenetic imprints are established in the parental germline remain poorly understood. In this study, we used Caenorhabditis elegans as a model system and demonstrated that a key node of metabolism-Pod-2, an acetyl-CoA carboxylase, together with vitellogenins (Vits), cholesterol-binding/transport proteins, guide establishment of the acquired transgenerational epigenetic modifications H3K27me3 in the parental germline. The loss of function of a Vit; its transporter or receptor; or its binding partner, pod-2, resulted in the loss of acquired epigenetic memory in the germline. Our findings indicate that lipid metabolism is a critical mediator for establishing transgenerational epigenetic imprints in the germline.

Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non-homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability.This article has an associated First Person interview with the first author of the paper.