Epigenetics of Down Syndrome

唐氏综合症的表观遗传学

• 批准号: 9977004
• 负责人: Benjamin Tycko
• 金额: $ 126.01万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977004
• 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; 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）的发病机制对于以下方面的研究具有重要意义