Transgenerational epigenetic inheritance mediated by the acetyltransferase MYS-2/MOF in the pathogenesis of Alzheimer’s disease

Abstract Background Although autosomal-dominant inheritance is believed to be an important cause of familial clustering AD (FAD), it covers only a small proportion of FAD incidence. Epigenetic memory has been suggested an alternative mechanism to explain transgenerational phenotypes in animals, and may contribute to intergenerational AD pathogenesis.Methods We employed the methods of RNA interference, gene mutation, treatment of inhibitors or agonists, and Western blot, to investigate the roles of acetyltransferase MYS-2/MOF and its mediated H4K16 in transgenerational heredity of AD pathogenesis in C. elegans and cell AD models. To validate our findings, we also analyzed the MOF(KAT8) expression data in AD patients from Alzdata. Fluorescence staining and ELISA were performed to detect Aβ accumulation or lysosomal activities. Gene expression patterns and the potential target genes associated with AD pathogenesis were analyzed in parental and progeny generations using RNA-seq, ChIP-seq, and ChIP-qPCR.Results Our data in vivo showed that mys-2 of Caenorhabditis elegans that encodes a MYST acetyltransferase responsible for H4K16 acetylation modulated AD occurrence. The phenotypic improvements in the parent generation caused by mys-2 deficiency were passed to their progeny due to epigenetic memory, which resulted in similar H4 acetylation levels among the candidate target genes of MYS-2 and similar gene expression patterns of the AD-related pathways. Furthermore, the ROS/CDK-5/ATM pathway functioned as an upstream activator of MYS-2. Furthermore, we showed that the mammalian ortholog MOF had the same role in AD pathogenesis.Conclusions Our study indicated that AD could be inherited transgenerationally via epigenetic mechanisms, providing a new insight into our understanding of the etiology and inheritance of FAD.