Genetic-epigenetic interactions in paternal transgenerational inheritance of metabolic disorders

Parental environmental exposures can strongly influence descendant risks for adult disease. Metabolic disorders arise from the intersection of environmental and genetic risk factors, with epigenetic inheritance being at the center of the familial cycle of transgenerational disease. How paternal high-fat diet changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. Using a genetic model of epigenetic inheritance, we investigated the role of histone H3 lysine 4 methylation (H3K4me3) in the paternal transmission of metabolic dysfunction. We show that obesity-induced alterations in sperm H3K4me3 associated with offspring phenotypes and corresponded to embryonic and placental chromatin profiles and gene expression. Transgenerational susceptibility to metabolic disease was only observed when grandsires had a pre-existing genetic predisposition to metabolic dysfunction that was associated with enhanced alterations to sperm H3K4me3. 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. Overall design: Examination of sperm H3K4me3 in wildtype or KDM1A transgenic male mice fed either a low-fat or high-fat diet, examination of liver total RNA in wildtype KDM1A transgenic male mice fed either a low-fat or high-fat diet and in their male and female descendants (F1 and F2)

亲本环境暴露可显著影响子代罹患成年疾病的风险。代谢性疾病由环境与遗传风险因子共同作用引发，表观遗传（epigenetic inheritance）是跨代疾病家族性循环的核心机制。父本高脂饮食如何改变精子染色质，进而导致子代罹患代谢性疾病的具体机制仍存在争议且尚未明确。本研究借助表观遗传的遗传模型，探究了组蛋白H3赖氨酸4甲基化（histone H3 lysine 4 methylation, H3K4me3）在代谢功能异常的父系传递中的作用。研究发现，肥胖诱导的精子H3K4me3改变与子代表型相关，且与胚胎及胎盘的染色质图谱和基因表达模式相契合。仅当父系祖父本身已具备代谢功能异常的遗传易感性，且该易感性与精子H3K4me3的改变程度增强相关时，才可观察到代谢性疾病的跨代易感性。这种基于非DNA的遗传认知，有望加深我们对环境如何塑造遗传力的理解，并为疾病预防提供全新途径。
实验设计：对喂食低脂或高脂饮食的野生型或KDM1A转基因雄性小鼠的精子H3K4me3进行检测；同时对喂食低脂或高脂饮食的野生型及KDM1A转基因雄性小鼠，以及其雄性和雌性子代（F1及F2代）的肝脏总RNA进行检测。