Epigenetic mechanisms and genes that regulate adipose tissue expansion

调节脂肪组织扩张的表观遗传机制和基因

• 批准号: 8616203
• 负责人: Robert A Koza
• 金额: $ 24.53万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616203
• 关键词: Epigenetic; mechanisms; genes; regulate; adipose

DESCRIPTION (provided by applicant): The global obesity epidemic is caused by multifactorial interactions between inherited allelic variation and the environment. Other components of obesity, based on variations in epigenetic programming, have been established by human epidemiological and animal studies that link nutritional status in utero and during early post-natal growth to the development of obesity and diabetes in adults. However, the mechanisms associated with these epigenetic contributions to obesity are not well understood. To identify epigenetic determinants of obesity, global analyses of gene expression was used to identify gene targets that are associated with phenotypic variations in the development of diet-induced obesity in a genetically identical population of mice. These analyses identified a set of genes that included imprinted developmental genes, antagonists of Wnt signaling and genes of angiogenesis and vascularization. Two of these genes, mesoderm specific transcript (Mest); a maternally imprinted gene localized in the endoplasmic reticulum/Golgi apparatus where it may function as a lipase or acyltransferase based on homology with members of the 1/2 hydrolase superfamily; and, bone morphogenetic protein 3 (Bmp3), an antagonist of bone formation that may act as an agonist of adiposity, are highly and coordinately expressed when fat mass is rapidly expanding. Mest and Bmp3 expression was shown to be elevated in adipose tissue biopsies of juvenile mice destined to develop diet-induced obesity as adults suggesting that molecular changes regulating these genes have been established prior to feeding a high fat diet. The coordinated expression and positive association of Mest and Bmp3 with variations of fat mass expansion in genetically identical mice suggests that epigenetic mechanisms are involved in their regulation. The studies in this proposal will determine the functional role for Mest and Bmp3 in fat mass expansion by using mouse models (Aim 1) and primary cell lines (Aim 2) with adipose tissue specific deletions for both genes; and, to uncover epigenetic mechanisms that regulate Mest and Bmp3 (Aim 3) by identifying changes in chromatin structure that are associated with their variable expression in adipose tissue of inbred mice. Understanding the mechanisms that regulate Mest and Bmp3 and how these genes control fat mass expansion could identify novel therapeutic targets for the treatment of obesity.

描述（由申请人提供）：全球肥胖病流行是由继承等位基因变异与环境之间的多因素相互作用引起的。人类流行病学和动物研究已经建立了基于表观遗传学编程的变化的其他组成部分，该研究已建立了子宫内营养状况以及产后早期生长期间的营养状况与成人肥胖和糖尿病的发展。但是，与这些表观遗传学贡献有关的机制尚不清楚。为了鉴定肥胖的表观遗传决定因素，使用对基因表达的全球分析来识别与表型变异相关的基因靶标，而在遗传上相同的小鼠群体中，饮食诱导的肥胖的发展。这些分析确定了一组基因，其中包括印迹的发育基因，Wnt信号的拮抗剂以及血管生成和血管形成的基因。其中两个基因，中胚层特异性转录本（MEST）；基于与1/2水解酶超级家族成员的同源性，它可以在内质网/高尔基体中定位的母体印迹基因，在内质网/高尔基体中，它可以作为脂肪酶或酰基转移酶发挥作用；并且，骨形态发生蛋白3（BMP3）是骨形成的拮抗剂，可能充当肥胖的激动剂，当脂肪质量迅速扩张时，可以高度且协调地表达。 Mest和Bmp3表达被证明在脂肪组织活检中升高，这些小鼠的脂肪组织活检有望发展为饮食引起的肥胖症，因为成年人表明，在喂养高脂饮食之前已经建立了调节这些基因的分子变化。 MEST和BMP3与遗传相同小鼠中脂肪质量膨胀变化的协调表达和正相关性表明，表观遗传机制参与其调节。该提案中的研究将通过使用小鼠模型（AIM 1）和原代细胞系（AIM 2）在脂肪质量扩张中确定MEST和BMP3的功能作用，并具有两个基因的脂肪组织特异性缺失；并且，通过识别与染色质结构的变化相关的变化，这些变化与它们在近交小鼠的脂肪组织中的可变表达相关，从而发现调节MEST和BMP3的表观遗传机制（AIM 3）。了解调节MEST和BMP3的机制，以及这些基因如何控制脂肪质量的扩张可以鉴定出新的治疗靶标以治疗肥胖症。