Epigenetic Changes with Age in Hematopoietic Stem Cells

描述(由申请人提供)：表观基因组的改变已被证明是发育和分化过程中基因表达的一层调节。染色质修饰和DNA甲基化在这些过程中都很重要。人们对衰老过程中的这些变化知之甚少，但从其中一种Co-Pis(EM)的实验室研究中，已经记录了肝脏和黑素细胞随年龄的变化。这项应用汇集了一个多学科团队，以生成与基因表达的激活和抑制相关的全球、基因组范围的染色质修改图，以及DNA中胞苷甲基化位置的全球图。DNA甲基化已被证明与染色质修饰的相关性大于与特定DNA序列的相关性。我们建议对小鼠造血干细胞(HSC)进行这些研究，Co-PI(MG)已经表明，小鼠和老年小鼠之间的基因表达发生了显著变化，并且移植到致死照射的受者身上的能力降低。这些图谱将使用高通量测序生成，从而实现核苷酸水平的区分。此外，为了测试IGF1通路在染色质修饰中的作用，我们将检测来自长寿小鼠模型的HSC，生长激素释放激素受体突变体小鼠。此外，老龄化社区将研究的第二个模型是过早衰老综合症，在该综合征中，P53蛋白稳定，动物寿命缩短，具有加速衰老的特征。这些研究产生的数据将成为老龄社区的资源，并将通过NCBI基因表达总览网站提供给科学界。这笔赠款将能够招聘四名新人员，并可在两年内完成，从而实现ARRA方案的目标之一。 公共卫生相关性：该应用程序将生成有关造血干细胞随年龄增长的表观基因组的数据，这些数据将立即发布给科学界。这个项目需要高通量的技术和一支多学科的调查团队。这笔赠款将对ARRA的指导方针作出回应，雇用目前不在调查人员实验室工作的四名个人。

DESCRIPTION (provided by applicant): Alterations in the epigenome have been shown to be a layer of regulation of gene expression in development and differentiation. Both chromatin modifications and DNA methylation are important in these processes. Relatively little is known about these changes in aging, but from studies done in the laboratory of one of the Co-PIs (EM), alterations in the liver and in melanocytes with age have been documented. This application brings together a multi- disciplinary team to generate a global, genome wide map of chromatin modifications associated with both activation and repression of gene expression as well as a global map of cytidine methylation sites in the DNA. DNA methylation has been shown to have more of a correlation with chromatin modifications than with specific DNA sequence. We propose to carry out these studies on murine hematopoietic stem cells (HSC) which have been shown by the Co-PI (MG) to have significant changes in gene expression between young and old mice as well as reduced ability to engraft upon transplantation to lethally irradiated recipients. The maps will be generated using high throughput sequencing which gives nucleotide level discrimination. Further, to test the role of the IGF1 pathway in chromatin modification, we will examine the HSC from a long lived mouse model, the growth hormone releasing hormone receptor mutant, the Little mouse. In addition, a second model of interest to the aging community that will be studied is the premature aging syndrome in which the p53 protein is stabilized and the animals have a shortened lifespan with accelerated characteristics of aging. Data generated from these studies will be a resource for the aging community and will be made available to the scientific community through the NCBI Gene Expression Omnibus site. This grant will enable the recruitment of four new personnel and can be completed within two years thus fulfilling one of the goals of the ARRA program. PUBLIC HEALTH RELEVANCE: This application will generate data on the epigenome of hematopoietic stem cells with age which will be released to the scientific community immediately. This project requires high throughput technology and a team of multidisciplinary investigators. The grant will respond to the ARRA guidelines by employing four individuals not currently working in the laboratories of the investigators.