Epigenetic Modifiers in Down Syndrome

唐氏综合征(DS；21三体；+21)的一个显著特征是严重程度广泛，主要特征在个体之间存在很大差异。这些疾病包括心脏缺陷、基线认知功能和与年龄相关的痴呆，以及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，甚至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改变的DNA甲基化模式，可能会影响这些表型中的一些或全部。我们有大量的初步数据支持这一假设，来自我们开发的名为MSNP的剖析方法，以及来自补充平台LLumina Infinium的化验。在这个高度互动的项目中，我们将对广泛年龄范围的DS患者的外周血白细胞(PBL)DNA进行MSNP和LLumina Infinium检测，包括收集独特的最年长的老年幸存者，并将结果与相同年龄范围的正常对照组进行比较。我们将用亚硫酸氢盐焦磷酸测序验证这种表观遗传学分析，并将甲基化与 在400多名患有DS的成年人中，甲基化程度与贫血、自身免疫紊乱和反复感染的严重程度相关的指标和SNP基因座。同时，我们将使用细胞培养和小鼠模型对最优先的差异甲基化基因进行直接功能研究。虽然这个项目的重点是与血细胞相关的表型，但这些数据可能还会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)的DNA甲基化变化提供一个原则证明。

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.