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Role of SRY in transgenerational transmission of alcohol epigenetic marks on proopiomelanocortin gene

SRY在阿黑皮素原基因酒精表观遗传标记跨代传递中的作用

基本信息

批准号：
10190731
负责人：
DIPAK KUMAR SARKAR
金额：
$ 34.88万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190731
关键词：
Address Affect Alcohol consumption Alcohol-Related Disorders Alcohols Animal Model Animals Binding Binding Sites Biological Markers Child Complex Corticosterone DNA Data Development Disease Drug abuse Drug usage Electroporation Emotional Disturbance Endocrine Environmental Risk Factor Epigenetic Process Ethanol Excision Fertilization Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome Fetal alcohol effects Gametogenesis Gene Expression Gene Expression Regulation Generations Genes Genetic Genomic DNA Germ Cells Grant Growth Health Heritability Hormones Human Hypothalamic structure Immune Immune System Diseases Immune response Inbred F344 Rats Interferon Type II Interferons Knowledge Learning Disabilities Life Link Malignant Neoplasms Mediating Medical Methods Methylation Modeling Modification Molecular Mothers Mutation Analysis National Institute on Alcohol Abuse and Alcoholism Neuropeptides Neurosecretory Systems Parents Patients Pharmaceutical Preparations Phenotype Plasmids Population Pro-Opiomelanocortin Process Production Promoter Regions Public Health Rattus Reporter Research Risk Rodent Model Role Series Spermatocytes Stress Techniques Testing Third Pregnancy Trimester Tissues Transfection Variant Y Chromosome alcohol and other drug alcohol effect alcohol exposure base behavioral phenotyping beta-Endorphin biological adaptation to stress chromatin immunoprecipitation cytokine demethylation drug induced behavior endophenotype epidemiology study epigenetic therapy expression vector fetal grandparent immune function immune system function imprint in vivo interest knock-down male melanocortin receptor methylation pattern next generation novel offspring overexpression peptide B preference prenatal prevent promoter pyrosequencing response sex sperm cell sry Genes transcription factor transgenerational epigenetic inheritance transmission process young adult

项目摘要

Project Summary/Abstract Children and young adults who were exposed to alcohol during fetal life often show fetal alcohol spectrum disorders (FASD) consisting of learning disabilities, emotional disturbances, stress abnormalities and immune incompetence. Furthermore, some grandparents who had alcohol-related medical problems often had grandchildren with a higher rate of fetal alcohol syndrome than those grandparents without alcohol-related medical problems. Epidemiological studies also have shown association of paternal alcohol consumption with deficiencies in offspring—effects which are typically found with maternal alcohol exposure. However, the process underlying the heritability of alcohol-induced health issues is not clearly understood. Our recent studies identified an epigenetic mechanism in the heritable effect of fetal alcohol on stress response abnormalities and immune dysfunctions. These studies showed that the proopiomelanocortin (Pomc) gene, which negatively controls the functions of the stress axis and stimulates the functions of the immune systems, is hypermethylated while the response of stress axis hormones and the production of the cytokine interferon-γ (IFN-γ) is dysregulated in fetal alcohol exposed offspring for three generations via the male germline. However, the process by which these epigenetic variants induced by fetal alcohol are transmitted from parents to offspring through multiple generations has not been established. We hypothesize that a transcription factor like sex-determining region Y (SRY), which has significant control over Pomc gene expression, undergoes heritable epigenetic modifications by fetal alcohol exposures that in turn modify the expression of the Pomc gene and its endophenotypes. The objective of this proposal is to determine the heritable epigenetic effects of alcohol exposure during the prenatal period on SRY-mediated Pomc gene expression and its endophenotypes, i.e., the stress hormone response and IFN-γ production to an immune challenge, in isogenic Fischer 344 rats. This research aim will be achieved by determining the relationship between the fetal alcohol epigenetic marks on Pomc and its endophenotypes with the epigenetic marks on the Sry gene in the isogenic rat population in three generations of offspring, studying the interaction between SRY and Pomc at the molecular level, and evaluating whether increased methylation affects SRY interaction with the Pomc promoter and contributes to fetal alcohol effects on Pomc and its endophenotypes. Various state of the art techniques will be employed involving promoter methylation, promoter demethylation, promoter activity, mutational analysis, gene knock down, in vivo electroporation for gene overexpression, and stress and immune response studies. These studies will establish the process by which developmental alcohol exposure induces gene expression variants in the offspring and how they are transmitted to next generations. Knowledge on the process involved in the heritability of alcohol-induced epigenetic variants may help in establishing new biomarkers and novel epigenetic-based therapies for many alcohol-related disorders.

项目概要/摘要在胎儿时期接触酒精的儿童和年轻人通常会表现出胎儿酒精谱障碍（FASD），包括学习障碍、情绪障碍、压力异常和免疫障碍无能。此外，一些患有与酒精相关的健康问题的祖父母经常患有与没有酒精相关症状的祖父母相比，孙辈患有胎儿酒精综合症的比例更高医疗问题。流行病学研究还表明，父亲饮酒与后代的缺陷——通常在母亲接触酒精时发现的影响。然而，酒精引起的健康问题的遗传性背后的过程尚不清楚。我们最近的研究确定了胎儿酒精对应激反应的遗传效应的表观遗传机制异常和免疫功能障碍。这些研究表明，阿片黑皮质素原 (Pomc) 基因，它对压力轴的功能产生负面控制并刺激免疫系统的功能，过度甲基化，同时应激轴激素的反应和细胞因子干扰素-γ的产生 (IFN-γ) 在胎儿酒精暴露的后代中通过雄性种系的三代发生失调。然而，由胎儿酒精引起的这些表观遗传变异从父母传播到的过程多代的后代尚未确定。我们假设转录因子如性别决定区 Y (SRY) 对 Pomc 基因表达具有显着控制作用，胎儿酒精暴露造成的可遗传的表观遗传修饰，进而改变 Pomc 的表达基因及其内表型。该提案的目的是确定可遗传的表观遗传效应产前酒精暴露对 SRY 介导的 Pomc 基因表达及其内表型的影响，即等基因 Fischer 344 大鼠中对免疫挑战的应激激素反应和 IFN-γ 产生。该研究目标将通过确定胎儿酒精表观遗传标记之间的关系来实现等基因大鼠群体中 Sry 基因表观遗传标记对 Pomc 及其内表型的影响三代后代，在分子水平上研究SRY和Pomc之间的相互作用，以及评估甲基化增加是否会影响 SRY 与 Pomc 启动子的相互作用并有助于胎儿酒精对 Pomc 及其内表型的影响。将采用各种最先进的技术涉及启动子甲基化、启动子去甲基化、启动子活性、突变分析、基因敲入向下，用于基因过度表达的体内电穿孔以及应激和免疫反应研究。这些研究将确定发育时期酒精暴露诱导基因表达变异的过程以及它们如何传递给下一代。有关该过程所涉及的知识酒精诱导的表观遗传变异的遗传性可能有助于建立新的生物标志物和新的针对许多酒精相关疾病的表观遗传学疗法。