Maternal Programming of Gene Expression Through DNA Methylation

通过 DNA 甲基化进行基因表达的母体编程

基本信息

批准号：
7798217
负责人：
Michael Joseph Meaney
金额：
$ 21.11万
依托单位：
MCGILL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7798217
关键词：
Adrenal Glands Adult Adult Children Affect Animals Back Behavior Behavioral Biological Assay Brain Cardiovascular system Caring Cell Culture Techniques Cell model Cells Chemicals Chromatin Structure Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytosine DNA DNA Methylation DNA Sequence DNA-Protein Interaction Development Discipline of Nursing Elderly Embryo Environment Epigenetic Process Event Excision Exons Feedback Female Fetal Growth Retardation Fetus Fostering Frequencies Gene Expression Gene Mutation Gene Targeting Genes Genetic Transcription Glucocorticoid Receptor Glucocorticoids Glucose Grooming Health Hippocampus (Brain)Human Hypothalamic structure In Vitro Individual Differences Insecta Kidney Knowledge Lead Life Literature Long-Term Effects Longevity Mammals Maps Maternal Behavior Mediating Metabolic Methods Methylation Mitotic Modeling Molecular Mothers Mutation Neurons Neurosecretory Systems Nucleotides Nurses Nutrient Outcome Paper Phase Phenotype Physiology Pituitary Gland Predatory Behavior Pregnancy Process Promoter Regions Proteins Rattus Receptor Gene Reptiles Research Research Design Research Personnel Response Elements Rodent Role Serotonin Site Somatic Cell Specificity Stress Tactile Tissues Transcription Factor AP-2 Alpha Variant Work base chromatin immunoprecipitation demethylation early experience experience histone modification in utero in vivo kidney cell lipid metabolism maternal stress neonate novel offspring programs promoter pup receptor expression response serotonin 7 receptor sodium bisulfite trait

项目摘要

Maternal care of pups influences the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Thus, the adult offspring of mothers that naturally show an increased frequency of pup licking/grooming and arched back nursing (ie, High LG-ABN mothers) show more modest HPA responses to stress. These effects are, in part, mediated by changes in hippocampal glucocorticoid receptor (GR) gene expression. We propose a working model describing the cellular and molecular basis for this maternal effect. The changes in maternal care increase serotonin (5-HT) turnover in the hippocampus which, in turn, activates cAMP formation via a 5-HT7 receptor and to increase protein kinase A activity and increased expression of activator protein-2 (AP-2) and NGFI-A which transactivate GR gene transcription via direct interaction with relevant GR gene promoter sequences. The critical questions concerns the apparent perminance of these effects: How might maternal care program differences in gene expression over the lifespan of the offspring. Our studies are designed to examine hypothesis that such effects are mediated by structural changes in DNA sequences located at specific sites within the promoter region of the GR gene. These studies use both in vivo and in vitro approaches to examine how maternal care alters DNA methylation and the relationship between such chemical alterations of the DNA, chromatin structure, gene expression and physiology. The methods include analysis of single nucleotide methylation using sodium bisulfite mapping, histone modifications and DNA-protein interactions with chromatin immunoprecipitation assays. We believe that these studies hold the possibility of providing a clear description of the mechanisms by which maternal care exerts long-term effects over gene expression in the brain and thus of phenotypic development. In essence, these studies directly examine gene X environment interactions in relation to specific, functional trait. Finally, although normally loath to use such descriptions, to the best of our knowledge these studies potentially provide the first description of structural changes in DNA in response to a post-mitotic, environmental event, and may ultimately provide the initial studies of environmentally-induced plasticity in DNA methyation and chromatin structure over the lifespan.

幼崽的孕产妇护理会影响下丘脑 - 垂体 - 肾上腺（HPA）对大鼠的压力。因此，母亲的成年后代自然显示出幼犬频率的增加舔/修饰和拱形的护理（即高LG-ABN母亲）显示出对HPA的更温和的回应压力。这些作用部分是由海马糖皮质激素受体（GR）基因的变化介导的表达。我们提出了一个工作模型，描述了该母体的细胞和分子基础影响。孕产妇护理的变化增加了海马中的5-羟色胺（5-HT）营业额通过5-HT7受体激活cAMP的形成，并增加蛋白激酶A活性并增加激活蛋白2（AP-2）和NGFI-A的表达，通过直接进行反式激活GR基因转录与相关的GR基因启动子序列的相互作用。关键问题涉及明显的这些影响的允许：孕产妇护理程序在基因表达中如何在后代的寿命。我们的研究旨在研究假设，即这种影响是由 DNA序列的结构变化位于GR基因启动子区域内的特定位点。这些研究都使用体内和体外方法来检查产妇护理如何改变DNA 甲基化和这种化学改变的DNA，染色质结构，基因之间的关系表达和生理。该方法包括使用钠对单核苷酸甲基化的分析亚硫酸盐图，组蛋白修饰和与染色质免疫沉淀的DNA-蛋白质相互作用测定。我们认为，这些研究的可能性可以清楚地描述孕产妇护理对大脑中基因表达的长期影响以及表型的发展。本质上，这些研究直接研究了基因x环境相互作用特定的功能性状。最后，尽管通常不愿意使用这种描述，但尽力而为知识这些研究可能会为DNA中的结构变化提供首次描述。有线后的环境事件，最终可能提供对环境诱导的初步研究 DNA甲基化和染色质结构的可塑性。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.

DOI：
10.1038/nn.2270
发表时间：
2009-03
期刊：
NATURE NEUROSCIENCE
影响因子：
25
作者：
McGowan, Patrick O.;Sasaki, Aya;D'Alessio, Ana C.;Dymov, Sergiy;Labonte, Benoit;Szyf, Moshe;Turecki, Gustavo;Meaney, Michael J.
通讯作者：
Meaney, Michael J.

Diet and the epigenetic (re)programming of phenotypic differences in behavior.