Maternal Programming of Gene Expression Through DNA Methylation

哺乳对下丘脑-垂体-肾上腺(HPA)反应的影响 大鼠的应激反应。因此，自然地表现出幼崽出生频率增加的母亲的成年后代 舔舔/梳理和弓背哺乳(即高LG-ABN母亲)对HPA的反应更温和 压力。这些效应在一定程度上是通过海马糖皮质激素受体(GR)基因的变化来实现的 表情。我们提出了一个工作模型，描述了这种母体的细胞和分子基础 效果。产妇护理的变化增加了海马体中5-羟色胺(5-HT)的周转，进而， 通过5-HT7受体激活cAMP的形成并增加蛋白激酶A的活性 激活蛋白-2(AP-2)和神经生长因子-A(NGFI-A)直接反式激活GR基因转录 与相关GR基因启动子序列的相互作用。关键问题与显而易见的 这些影响的持续性：产妇保健如何计划基因表达的差异 后代的寿命。我们的研究旨在检验这样的影响是由 位于GR基因启动子区特定位置的DNA序列的结构变化。 这些研究使用体内和体外方法来研究产妇护理如何改变dna。 甲基化及其与DNA、染色质结构、基因等化学变化的关系 表情和生理学。这些方法包括使用钠进行单核苷酸甲基化分析。 染色质免疫沉淀的亚硫酸氢盐定位、组蛋白修饰和DNA-蛋白质相互作用 化验。 我们认为，这些研究有可能通过以下方式提供对这些机制的明确描述 哪种产妇护理对大脑中的基因表达产生长期影响，从而对表型产生影响 发展。从本质上讲，这些研究直接考察了基因与环境的相互作用与 特定的、功能性的特征。最后，尽管通常不愿使用这样的描述，但尽我们所能 知识这些研究潜在地提供了对DNA结构变化的第一个描述 有丝分裂后的环境事件，并可能最终提供环境诱导的初步研究 寿命中DNA甲基化和染色质结构的可塑性。

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.