Epigenetic Modifiers in Down Syndrome

唐氏综合症的表观遗传修饰剂

• 批准号: 7976426
• 负责人: Benjamin Tycko
• 金额: $ 27.79万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976426
• 关键词: Adult; Affect; Age; Aged, 80 and over; Anemia; Aneuploidy; Area; Autoimmune Diseases; Autoimmunity; Biological Assay; Biology; Blood Cells; Brain; Candidate Disease Gene; Caring; Cell Culture Techniques; Cell physiology; Childhood Leukemia; Chromosomes; Chromosomes, Human, Pair 21; Collection; Congenital Heart Defects; Congenital chromosomal disease; DNA; DNA Methylation; Data; Data Analyses; Dementia; Development; Down Syndrome; Employee Strikes; Epigenetic Process; Future; Genes; Genetic; Genomics; Individual; Individual Differences; Infection; Intellectual functioning disability; Knock-out; Leukocytes; Medical; Methods; Methylation; Organ; Pathogenesis; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Predisposition; Recurrence; SNP genotyping; Sampling; Severities; Site; Survivors; Syndrome; Testing; Tissues; Transgenic Mice; Translating; Triage; Update; Variant; Work; age related; bisulfite; clinical phenotype; cognitive function; cohort; indexing; insight; mRNA Expression; mouse model; neutrophil; peripheral blood; research study; response

A striking feature of Down syndrome (DS; trisomy 21; +21) is the wide range of severity, with strong inter-individual differences in its major features. These include cardiac defects, baseline cognitive function and age-related dementia, as well as several important phenotypes due to altered development and function of blood cells (e.g., childhood leukemias, anemia, autoimmune disorders, and susceptibility to infections). In most cases the genetic or epigenetic factors underlying this variation, and indeed the pathogenesis of the phenotypes themselves, remain largely unknown. Here we hypothesize that the relevant tissues in people with +21 may have accumulated altered patterns of DNA methylation on chromosome 21 and on other chromosomes, potentially affecting some or all of these phenotypes. We have substantial preliminary data supporting this hypothesis, from a profiling method that we developed called MSNP, and from a complementary platform, lllumina Infinium assays. In this highly interactive project we will carry out MSNP and lllumina Infinium assays on peripheral blood leukocyte (PBL) DNAs from people with DS spanning a wide range of ages, including a unique collection of the oldest old survivors, comparing the results with normal controls spanning the same age range. We will validate this epigenetic analysis with bisulfite Pyrosequencing, and correlate the methylation indices and SNP genotypes at the loci with strongest differential methylation with the severity of anemia, autoimmune disorders, and recurrent infections in more than 400 adults with DS. In parallel, we will carry out direct functional studies of the highest priority differentially methylated genes using cell culture and mouse models. While this project is focused on blood cell-related phenotypes, the data may additionally provide a proof-of-principle for future studies of altered DNA methylation in other major organs, including the brain, in this important chromosomal disorder.

唐氏综合症（DS；21 三体；+21）的一个显着特征是严重程度范围广泛，其主要特征存在强烈的个体差异。这些包括心脏缺陷、基线认知功能和年龄相关性痴呆，以及由于血细胞发育和功能改变而导致的几种重要表型（例如儿童白血病、贫血、自身免疫性疾病和感染易感性）。在大多数情况下，这种变异背后的遗传或表观遗传因素，以及表型本身的发病机制，在很大程度上仍然未知。在这里，我们假设 +21 患者的相关组织可能在 21 号染色体和其他染色体上积累了 DNA 甲基化模式的改变，可能影响部分或全部这些表型。我们有大量初步数据支持这一假设，这些数据来自我们开发的 MSNP 分析方法和补充平台 lllumina Infinium 检测。在这个高度互动的项目中，我们将对不同年龄段的 DS 患者（包括最年长的幸存者的独特集合）的外周血白细胞 (PBL) DNA 进行 MSNP 和 lllumina Infinium 检测，并将结果与​​相同年龄范围的正常对照进行比较。我们将使用亚硫酸氢盐焦磷酸测序验证这种表观遗传学分析，并将甲基化关联起来 在超过 400 名 DS 成人中，差异甲基化最强的位点的指数和 SNP 基因型与贫血、自身免疫性疾病和复发感染的严重程度有关。与此同时，我们将利用细胞培养和小鼠模型对最高优先级的差异甲基化基因进行直接功能研究。虽然该项目的重点是与血细胞相关的表型，但这些数据还可能为未来研究这种重要的染色体疾病中其他主要器官（包括大脑）中 DNA 甲基化的改变提供原理证明。