Epigenetic Modifiers in Down Syndrome

唐氏综合症（DS; trisomy 21; +21）的一个显著特征是严重程度范围广，其主要特征存在强烈的个体间差异。这些包括心脏缺陷、基线认知功能和与年龄相关的痴呆，以及由于血细胞发育和功能改变引起的几种重要表型（例如，儿童白血病、贫血、自身免疫性疾病和对感染的易感性）。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，在很大程度上仍然是未知的。在这里，我们假设+21人的相关组织可能在21号染色体和其他染色体上积累了改变的DNA甲基化模式，可能影响部分或全部这些表型。我们有大量的初步数据支持这一假设，这些数据来自我们开发的一种称为MSNP的分析方法，以及来自互补平台lllumina Infinium分析。在这个高度互动的项目中，我们将对来自不同年龄的DS患者的外周血白细胞（PBL） dna进行MSNP和lllumina Infinium检测，包括最年长的老年幸存者的独特收集，并将结果与相同年龄范围的正常对照进行比较。我们将用亚硫酸氢盐焦磷酸测序验证这一表观遗传分析，并将甲基化联系起来

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.