Multigenerational epigenetic programming induced by paternal obesity and prediabetes

父亲肥胖和糖尿病前期诱导的多代表观遗传编程

• 批准号: 9752558
• 负责人: DARIO BOFFELLI
• 金额: $ 55.74万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752558
• 关键词: Adult; Affect; Attention; Biological Markers; Comorbidity; Correlation Studies; DNA; Data; Defect; Developed Countries; Developing Countries; Diabetes Mellitus; Disease; Embryo; Environmental Exposure; Epidemic; Epigenetic Process; Exposure to; Fatty Liver; Gene Expression; Generations; Genetic Models; Genetic Transcription; Genome; Germ Lines; Habits; Health Services; Heritability; High Fat Diet; Human; Hyperinsulinism; Interruption; Intervention; Laboratories; Lead; Liver; Malnutrition; Measures; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Methods; Methylation; MicroRNAs; Mus; Nutritional; Obesity; Outcome; Overnutrition; Parents; Pathologic; Pattern; Penetrance; Phenotype; Policies; Prediabetes syndrome; Pregnancy; Prevention Measures; Risk; Small RNA; Societies; Specific qualifier value; Syndrome; System; Testing; Therapeutic; Transcript; Transcription Process; United States; Work; base; epigenomics; genetic information; genetic variant; impaired glucose tolerance; in utero; insight; intergenerational; male; metabolic phenotype; mouse model; non-genetic; novel; nutrition; obesity in children; obesity risk; offspring; prevent; programs; public health relevance; response; sperm cell; transcriptome; transmission process; zygote

“Multigenerational epigenetic programming induced by paternal obesity and prediabetes” ABSTRACT Obesity and its related co-morbidities have reached epidemic proportions in the United States and other developed countries, posing an unprecedented challenge to health services. We find that a single generation of paternal obesity and prediabetes programs male offspring with a latent metabolic defect that is exposed by overnutrition. The latent phenotype is transmitted paternally for two generations without further exposure to paternal obesity. Paternal transmission is associated with changes in the sperm small RNAs that are predicted to regulate transcriptional processes. This non-genetic transmission of phenotypes across generations may be a significant contributor to the risk of obesity, and may require intervention and prevention measures across multiple generations. Understanding the scope and the mechanism of this heritable epigenetic programming phenomenon will be critical in developing new strategies to manage or prevent the effects of paternal obesity. This study has the potential to identify biomarkers that could be used to characterize the syndrome in humans. We propose to determine (1) if multiple generations of exposure to paternal obesity and prediabetes amplify the metabolic phenotype in subsequent generations, and/or increase its heritability; (2) the mechanism of paternal inheritance of the metabolic phenotype, through epigenetic changes in the sperm of affected sires; (3) the transcriptional changes that occur in the early embryo in response to epigenetic changes in the sperm. The concept that environmental exposures can induce heritable epigenetic states has received much recent attention, but the subject is very poorly understood and documented. Our experimental system permits a direct test of the epigenetic inheritance model: genetic variants can be ruled out as a factor in transmission because we study isogenic mice, transmission through the paternal line rules out in utero metabolic exposure as a cause, and the high penetrance of the metabolic phenotype makes it amenable to mechanistic studies. The unexpected multigenerational effect of paternal obesity/prediabetes on the metabolism of genetically identical offspring challenges established views on the causes of obesity. This study will provide evidence that there is an inborn but non-genetic component to the risk of obesity, insights into the mechanisms by which that risk is created and transmitted, and a system amenable to further study of the phenomenon.

“由父亲肥胖和糖尿病前期引起的多代表观遗传学编程” 抽象的 肥胖及其相关的合并症在美国和其他 发达国家对卫生服务提出了前所未有的挑战。我们发现一代人 父亲肥胖和糖尿病前期计划的男性后代，其潜在代谢缺陷被暴露 营养不良。潜在的表型是在两代人的父子上传播的，而无需进一步暴露 Patanal观察。 Patanal的传播与精子小RNA的变化有关，这些变化被预测 调节转录过程。在世代相传的这种非遗传传播可能是 导致肥胖风险的重要贡献者，可能需要跨越干预和预防措施 多代。了解这种可遗传的表观遗传编程的范围和机制 现象对于制定新策略来管理或防止父亲肥胖的影响至关重要。 这项研究有可能识别可用于表征人类综合征的生物标志物。 我们建议（1）是否有多​​代父亲肥胖和糖尿病前期的暴露 随后几代的代谢表型和/或增加其遗传力； （2）机制 代谢表型的父亲遗传，通过受影响的父亲的精子的表观遗传变化； （3） 早期胚胎对精子的表观遗传变化而发生的转录变化。 环境暴露会诱发可遗传的表观遗传状态的概念已获得了许多最近 注意，但是对主题的理解和记录很差。我们的实验系统允许直接 表观遗传遗传模型的测试：可以将遗传变体排除为传播的因素，因为 我们研究等生小鼠，通过父亲系的传播在子宫代谢暴露中排除的作为一个 原因，以及代谢表型的高渗透性使其适合机械研究。 父亲肥胖/糖尿病前期对一般代谢的意外多代作用 相同的后代挑战对肥胖的原因制定了观点。这项研究将提供证据表明 有一个天生的但非遗传的成分，肥胖的风险，对此机制的见解 风险是创建和传播的，并且可以进一步研究该现象。