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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：
9382377
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9382377
关键词：
Address Affect Alcohol consumption Alcohol-Related Disorders Alcohols Animal Model Animals Behavioral 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 System and Related Disorders 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 POMC gene Parents Patients Pharmaceutical Preparations Phenotype Plasmids Population Pro-Opiomelanocortin Process Production Promoter Regions Public Health Rattus Reporter Research Risk Rodent Model Role Series Stress Techniques Testing Third Pregnancy Trimester Tissues Transfection Variant Y Chromosome alcohol and other drug alcohol effect alcohol exposure base beta-Endorphin biological adaptation to stress chromatin immunoprecipitation cytokine demethylation drug induced behavior endophenotype epidemiology study 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.

项目总结/文摘