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: 9977169
• 负责人: DARIO BOFFELLI
• 金额: $ 23.84万
• 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 2021-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977169
• 关键词: Adult; Affect; Attention; Biological Markers; Correlation Studies; DNA; Data; Defect; Developed 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; comorbidity; 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.

“由父亲肥胖和前驱糖尿病引起的多代表观遗传规划” 摘要 肥胖及其相关的共病在美国和其他国家已经达到流行病的程度。 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的程序男性后代与潜在的代谢缺陷，是暴露于 营养过剩潜伏表型通过父系传递两代，无需进一步暴露于 父亲肥胖症父系传播与精子小RNA的变化有关， 来调节转录过程。这种表型的跨代非遗传传递可能是 肥胖风险的一个重要因素，并可能需要干预和预防措施， 多代人。了解这种可遗传的表观遗传编程的范围和机制 这一现象将是至关重要的，在发展新的战略，以管理或预防的影响，父亲肥胖。 这项研究有可能确定可用于描述人类综合征的生物标志物。 我们建议确定（1）多代人接触父亲肥胖和糖尿病前期是否会加剧 代谢表型在后代，和/或增加其遗传力;（2）的机制， 代谢表型的父系遗传，通过受影响公畜精子的表观遗传变化;（3） 在早期胚胎中发生的转录变化是对精子中表观遗传变化的反应。 环境暴露可以诱导可遗传的表观遗传状态的概念最近得到了广泛的关注。 注意，但这个问题是非常了解和记录。我们的实验系统允许直接 表观遗传模型的测试：遗传变异可以被排除为传播的一个因素， 我们研究了同基因小鼠，通过父系的传播排除了子宫内代谢暴露作为一种 原因，代谢表型的高突变率使其适合于机制研究。 父亲肥胖/前驱糖尿病对遗传代谢的意外多代影响 相同的后代挑战了关于肥胖原因的既定观点。这项研究将提供证据， 肥胖的风险有一个与生俱来但非遗传的因素， 风险被创造和传递，一个系统可以对这一现象进行进一步研究。