Hyperhomocysteinemia, S-adenosylhomocysteine Accumulation, and Epigenetics

描述(申请人提供)：血浆总同型半胱氨酸(THcy)水平升高，称为高同型半胱氨酸血症(HHcy)，前瞻性地与许多人类疾病的发病率和死亡率增加有关，包括冠心病、中风、痴呆症、阿尔茨海默病、糖尿病、骨质疏松症、癌症、神经管缺陷和肝脏脂肪变性。与tHcy升高相关的疾病的数量和种类表明，它可能会影响非常基本的细胞功能。同型半胱氨酸是S-同型半胱氨酸的中间代谢产物，它是甲基供体S-腺苷蛋氨酸甲基化反应的副产物。我们实验室和其他实验室的研究表明，血浆中tHcy的升高与组织中细胞内SAH的升高有关。由于SAH是甲基转移反应的有效抑制剂，例如那些参与基因表达调控的反应，这可能指出了一种可能的机制，将升高的tHcy与不同的疾病状态联系起来。因此，这项提议的总体目标是检验以下假设 严重的HHcy导致组织SAH升高，导致染色质甲基化受到抑制，并改变体内细胞基因的表达。拟议的实验将利用可诱导的遗传性和营养性小鼠模型，每种模型都通过不同的机制诱导严重的HHcy。有三个特定的目标：(1)确定HHcy是否与组织SAH水平升高以及DNA和组蛋白的整体低甲基化有关。(2)确定HHcy如何影响基因特异性转录水平、DNA和组蛋白甲基化。(3)检测SAH水解酶过表达能否逆转细胞的低甲基化状态和基因表达表型。实现这些目标将有助于理解tHcy升高导致疾病的机制，并将使我们对可能延缓或消除同型半胱氨酸相关疾病发病的潜在干预措施有新的见解。

DESCRIPTION (provided by applicant): Elevated levels of plasma total homocysteine (tHcy), termed hyperhomocysteinemia (HHcy), are associated prospectively with increased incidence and mortality of many human diseases including coronary heart disease, stroke, dementia, Alzheimer's disease, diabetes, osteoporosis, cancer, neural tube defects and steatosis of the liver. The number and variety of diseases associated with elevated tHcy suggests that it may affect very basic cellular functions. Homocysteine is an intermediary metabolite produced from the hydrolysis of S-adenosylhomocysteine (SAH), which is a by-product of methylation reactions involving the methyl-donor S-adenosylmethionine (SAM). Studies from our lab and others show that elevations in tHcy in plasma are associated with elevations of intracellular SAH in tissues. Since SAH is a potent inhibitor of methyl-transfer reactions, such as those involved in the regulation of gene expression, this could point to a possible mechanism linking elevated tHcy to diverse disease states. Therefore, the overall goal of this proposal is to test the hypothesis that severe HHcy causes elevations in tissue SAH that results in inhibition of chromatin methylation and alters cellular gene expression in vivo. The proposed experiments will utilize an inducible genetic and a nutritional mouse model that each induce severe HHcy by a different mechanism. There are three specific aims: (1) Determine if HHcy is associated with elevated tissue SAH levels and global hypomethylation of DNA and histones. (2) Determine how HHcy affects gene-specific transcript levels, DNA, and histone methylation. (3) Determine if overexpression of SAH hydrolase can reverse the hypomethylation and gene expression phenotypes. Achieving these aims will lead to understanding the mechanism by which elevated tHcy causes disease and will give us new insight into potential interventions that could delay or eliminate the onset of homocysteine related diseases.