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• W4220956838 endingPage "101463" @default.
• W4220956838 startingPage "101463" @default.
• W4220956838 abstract "Parental environmental exposures can strongly influence descendant risks for adult disease. How paternal obesity changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. The objective of this study was to assess (1) whether obesity induced by a high-fat diet alters sperm histone methylation; (2) whether paternal obesity can induce metabolic disturbances across generations; (3) whether there could be cumulative damage to the sperm epigenome leading to enhanced metabolic dysfunction in descendants; and (4) whether obesity-sensitive regions associate with embryonic epigenetic and transcriptomic profiles. Using a genetic mouse model of epigenetic inheritance, we investigated the role of histone H3 lysine 4 methylation (H3K4me3) in the paternal transmission of metabolic dysfunction. This transgenic mouse overexpresses the histone demethylase enzyme KDM1A in the developing germline and has an altered sperm epigenome at the level of histone H3K4 methylation. We hypothesized that challenging transgenic sires with a high-fat diet would further erode the sperm epigenome and lead to enhanced metabolic disturbances in the next generations.To assess whether paternal obesity can have inter- or transgenerational impacts, and if so to identify potential mechanisms of this non-genetic inheritance, we used wild-type C57BL/6NCrl and transgenic males with a pre-existing altered sperm epigenome. To induce obesity, sires were fed either a control or high-fat diet (10% or 60% kcal fat, respectively) for 10-12 weeks, then bred to wild-type C57BL/6NCrl females fed a regular diet. F1 and F2 descendants were characterized for metabolic phenotypes by examining the effects of paternal obesity by sex, on body weight, fat mass distribution, the liver transcriptome, intraperitoneal glucose, and insulin tolerance tests. To determine whether obesity altered the F0 sperm chromatin, native chromatin immunoprecipitation-sequencing targeting H3K4me3 was performed. To gain insight into mechanisms of paternal transmission, we compared our sperm H3K4me3 profiles with embryonic and placental chromatin states, histone modification, and gene expression profiles.Obesity-induced alterations in H3K4me3 occurred in genes implicated in metabolic, inflammatory, and developmental processes. These processes were associated with offspring metabolic dysfunction and corresponded to genes enriched for H3K4me3 in embryos and overlapped embryonic and placenta gene expression profiles. Transgenerational susceptibility to metabolic disease was only observed when obese F0 had a pre-existing modified sperm epigenome. This coincided with increased H3K4me3 alterations in sperm and more severe phenotypes affecting their offspring.Our data suggest sperm H3K4me3 might serve as a metabolic sensor that connects paternal diet with offspring phenotypes via the placenta. This non-DNA-based knowledge of inheritance has the potential to improve our understanding of how environment shapes heritability and may lead to novel routes for the prevention of disease. This study highlights the need to further study the connection between the sperm epigenome, placental development, and children's health.Paternal obesity impacts sperm H3K4me3 and is associated with placenta, embryonic and metabolic outcomes in descendants." @default.
• W4220956838 created "2022-04-03" @default.
• W4220956838 creator A5004698805 @default.
• W4220956838 creator A5016425529 @default.
• W4220956838 creator A5067257359 @default.
• W4220956838 creator A5070921061 @default.
• W4220956838 creator A5073823640 @default.
• W4220956838 date "2022-05-01" @default.
• W4220956838 modified "2023-10-17" @default.
• W4220956838 title "Sperm histone H3 lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction" @default.
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