Epigenetics of Down Syndrome

唐氏综合症的表观遗传学

• 批准号: 10200867
• 负责人: Benjamin Tycko
• 金额: $ 75.16万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200867
• 关键词: Address; Adult; Affect; Alleles; Alzheimer' s Disease; Aneuploidy; Architecture; Area; Autoimmunity; Autopsy; Bacterial Artificial Chromosomes; Binding Sites; Bioinformatics; Biological; Biological Assay; Biological Models; Brain; Cell Nucleus; Cells; Cerebrum; Chromatin; Chromosomal Duplication; Chromosomes; Critiques; DNA Methylation; DNA methylation profiling; Data; Development; Disease; Down Syndrome; Engineering; Epigenetic Process; Exhibits; Expression Profiling; Gene Dosage; Gene Expression; General Population; Genes; Genetic; Genetic Materials; Genetic Transcription; Genetic study; Genome; Genomics; Heart Abnormalities; Human; Individual; Intellectual functioning disability; Joints; Knock-out; Leukocytes; Life; Link; Lymphocyte; Malignant Neoplasms; Medical; Messenger RNA; Methylation; Modeling; Molecular; Mus; Mutation; Neuroglia; Neurons; Newborn Infant; Outcome; Paper; Pathogenesis; Pathway interactions; Pattern; Phenotype; Ploidies; Predisposition; Publishing; Quality of life; Recurrence; Research; Resistance; Shapes; Site; Specificity; Stains; Standardization; Syndrome; TF gene; Testing; Time; Tissues; Transgenes; Transgenic Model; Trisomy; Work; bisulfite sequencing; cell type; design; dosage; epigenetic profiling; epigenome; experimental study; fetal; gray matter; human tissue; improved; interstitial; mRNA Expression; methylation pattern; mouse Ts65Dn; mouse model; mutant; neoplastic; neuropsychiatric disorder; offspring; overexpression; response; success; transcription factor; transcriptome sequencing; whole genome

Achieving a better understanding of the pathogenesis of Down syndrome (DS; trisomy 21) is important for improving the quality of life of people with DS and for understanding major phenotypes, including intellectual disability, autoimmunity, cardiac defects, Alzheimer’s disease, and cancer susceptibility and resistance, which are prominent in DS and are also highly relevant to the general population. Recently we carried out epigenetic profiling, focusing on DNA methylation, in grey matter and purified neurons and glial cells from autopsy brains, as well as T-lymphocytes, from individuals with DS vs. matched normal controls. We found highly recurrent DS-specific differences in methylation patterns (DS-DM), and observed tissue-specificity of the DS-DM, onset of the altered methylation patterns at the fetal stage, and altered mRNA expression (DS-DE) of only a subset of the affected genes. We found that CpGs in specific classes of transcription factor binding sites (TFBS) were preferentially affected, implicating altered TFBS occupancy as a mechanism in shaping the patterns of DS-DM. Additionally, we carried out whole genome bisulfite sequencing (WGBS) on brains from mouse models of DS, compared to wild-type littermates, and found alterations in methylation patterns that significantly paralleled those in the human brains. Motivated by these findings, we now seek to answer three questions – all using well-controlled mouse models of DS carrying chromosomal triplications. First, to understand the molecular consequences of DS-DM we will identify DM genes in the mouse models and determine which of them have differential mRNA expression. We will address this question in purified cell types: T cells and GABAergic neurons. Second, we will test two hypotheses for the trans-acting mechanisms of DS-DM: (i) the abnormal methylation is due to over-expression of methylation pathway genes, including Dnmt3l and others, in the triplicated chromosome regions, and/or (ii) the abnormal patterns of methylation are shaped by overexpression of specific TF genes in the triplicated regions, leading to altered TFBS occupancy followed by altered CpG methylation in and around these sites. We will transfer segmental deletions and/or knockout alleles of individual genes into the DS mouse models to normalize gene dosage, and use WGBS and phenotyping to ask whether specific components of the DM and specific phenotypes are affected, respectively, in the offspring carrying the compound mutations. Third, we will apply state-of-the-art genomic assays to ask whether chromatin architecture within the cell nucleus is altered by the presence of the extra genetic material, and whether this alteration in turn affects DNA methylation, gene expression and phenotypes. Success of our project will identify effector and target genes for DS-DM and unravel the mechanisms underlying DS-DM. We expect that these data will significantly improve our understanding of DS pathogenesis and have broad implications for trans-acting genetic epigenetic interactions in other human developmental and neoplastic disorders that are associated with chromosomal aneuploidies.

更好地了解唐氏综合症（DS；21 三体）的发病机制对于 改善 DS 患者的生活质量并了解主要表型，包括智力 残疾、自身免疫、心脏缺陷、阿尔茨海默病以及癌症易感性和抵抗力， 在 DS 中很突出，并且与一般人群也高度相关。最近我们进行了表观遗传学研究。 分析，重点关注灰质中的 DNA 甲基化以及来自尸检大脑的纯化神经元和神经胶质细胞， 以及来自 DS 个体与匹配的正常对照的 T 淋巴细胞，我们发现高度复发。 甲基化模式 (DS-DM) 的 DS 特异性差异，以及观察到的 DS-DM 的组织特异性、发病情况 胎儿阶段甲基化模式的改变，以及仅一部分子集的 mRNA 表达改变 (DS-DE) 我们发现特定类别的转录因子结合位点 (TFBS) 中的 CpG 受到影响。 优先受影响，暗示 TFBS 占用的改变是塑造 DS-DM 模式的机制。 此外，我们对 DS 小鼠模型的大脑进行了全基因组亚硫酸氢盐测序 (WGBS)， 与野生型同窝小鼠相比，发现甲基化模式的改变与 受这些发现的启发，我们现在试图回答三个问题——全部使用 控制良好的携带染色体三倍体的 DS 小鼠模型 首先，了解分子机制。 DS-DM 的后果 我们将鉴定小鼠模型中的 DM 基因并确定其中哪些基因具有 我们将在纯化的细胞类型中解决这个问题：T 细胞和 GABA 能细胞。 其次，我们将测试 DS-DM 反式作用机制的两个假设：(i) 异常。 甲基化是由于甲基化途径基因的过度表达，包括 Dnmt3l 和其他基因， 三重染色体区域，和/或 (ii) 甲基化的异常模式是由过度表达形成的 三重区域中特定 TF 基因的变化，导致 TFBS 占据发生改变，随后 CpG 发生改变 我们将转移这些位点内及其周围的甲基化。 将单个基因导入 DS 小鼠模型以标准化基因剂量，并使用 WGBS 和表型分析来询问 后代中 DM 的特定成分和特定表型是否分别受到影响 第三，我们将应用最先进的基因组分析来询问是否携带复合突变。 细胞核内的染色质结构因额外遗传物质的存在而改变，并且 这种改变是否会反过来影响 DNA 甲基化、基因表达和表型。 该项目将确定 DS-DM 的效应基因和靶基因，并揭示 DS-DM 的潜在机制。 预计这些数据将显着提高我们对 DS 发病机制的理解，并具有广泛的应用前景。 反式遗传表观遗传相互作用对其他人类发育和肿瘤的影响 与染色体非整倍性相关的疾病。

项目成果

Hearing impairment in murine model of Down syndrome.

唐氏综合症小鼠模型的听力障碍。

• 发表时间: 2022
• 作者: Chen, Guang;Li, Li;McCall, Andrew;Ding, Dalian;Xing, Zhuo;Yu, Y Eugene;Salvi, Richard
• 通讯作者: Salvi, Richard

Coat Color-Facilitated Efficient Generation and Analysis of a Mouse Model of Down Syndrome Triplicated for All Human Chromosome 21 Orthologous Regions.

毛色促进唐氏综合症小鼠模型的高效生成和分析，该模型针对所有人类 21 号染色体直系同源区域进行三次重复。

• 发表时间: 2021
• 影响因子: 3.5
• 作者: Li, Yichen;Xing, Zhuo;Yu, Tao;Pao, Annie;Daadi, Marcel;Yu, Y Eugene
• 通讯作者: Yu, Y Eugene

SARS-CoV-2 Infection Causes Heightened Disease Severity and Mortality in a Mouse Model of Down Syndrome.

SARS-CoV-2 感染导致唐氏综合症小鼠模型的疾病严重程度和死亡率增加。

• 发表时间: 2024-02-28
• 影响因子: 4.7
• 作者: Pechous, Roger D;Malaviarachchi, Priyangi A;Xing, Zhuo;Douglas, Avrium;Crane, Samantha D;Theriot, Hayley M;Zhang, Zijing;Ghaffarieh, Alireza;Huang, Lu;Yu, Y Eugene;Zhang, Xuming
• 通讯作者: Zhang, Xuming