The Genetic and Epigenetic Basis for FSHD

FSHD 的遗传和表观遗传基础

• 批准号: 8232180
• 负责人: SILVERE M VAN DER MAAREL
• 金额: $ 17.54万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232180
• 关键词: Adult; Alleles; Binding Sites; Biological; Cells; Characteristics; Chromatin; Chromatin Structure; Chromosomes, Human, Pair 4; Clinical; Collaborations; Complex; Contracts; D4Z4; DNA; DNA Methylation; DNA Sequence; Data; Development; Disease; Distal; ES Cell Line; Embryonic Development; Enhancers; Epigenetic Process; Facioscapulohumeral Muscular Dystrophy; Fibroblasts; Functional disorder; Genetic; Genetic Enhancer Element; Genetic Transcription; Goals; Haplotypes; In Vitro; Lead; Mesenchymal Stem Cells; Methyl-CpG-Binding Protein 2; Modification; Myoblasts; Myopathy; Pathogenesis; Pathogenicity; Pathology; Patients; Process; RNA; RNA Binding; RNA Processing; Repression; Role; Structure; Testing; Transcript; Transcriptional Silencer Elements; Undifferentiated; Variant; base; chromatin protein; embryonic stem cell; established cell line; histone modification; human embryonic stem cell; insight; knock-down

PROJECT 1 The Genetic and Epigenetic Basis for FSIHD We have demonstrated that FSHD is caused by a contraction-cfepencfenf (FSHD1) or contractionindependent (FSHD2) change in chromatin structure of D4Z4 only when this contraction occurs on a specific genetic background (4qA161). This leads to the hypothesis that a change in D4Z4 chromatin structure on the 4qA161 haplotype is essential for FSHD pathology. Therefore, the long-term goal is to identify the specific DNA sequences and the epigenetic modifications that together confer pathogenicity to 4qA161. Aim 1 will identify and functionally characterize the disease haplotype-specific sequence variants of the distal repeat unit and flanking pLAM sequence. Recent studies identified this part of the FSHD locus as the minimal essential region; Aim 2 will identify and functionally characterize the chromatin structure of this minimal essential region test the hypothesis that the D4Z4 repeats regulate DUX4 expression and have a biological role in early embryonic development; and Aim 3 will determine the genetic and epigenetic characteristics of D4Z4 in human ES cells to establish the developmental role of D4Z4 in relation to the clinical features of FSHD.

项目1 FSIHD的遗传学和表观遗传学基础 我们已经证明FSHD是由收缩-cfepencfenf或收缩非依赖性引起的 (FSHD2)D4Z4染色质结构的变化仅当这种收缩发生在 特定遗传背景(4qA161)。这导致假设D4Z4染色质的变化 4qA161单倍型上的结构是FSHD的重要病理基础。因此，长期目标是 确定特定的DNA序列和共同赋予致病性的表观遗传修饰 4qA161。目标1将鉴定疾病单倍型特有的序列变异并对其进行功能表征 远端重复单位和侧翼PLAM序列。最近的研究确定了FSHD基因的这一部分 作为最小的基本区域；目标2将识别和功能表征染色质结构 这个最小的必要区域测试了D4Z4重复调控DUX4表达并具有 在早期胚胎发育中的生物学作用；目标3将决定遗传和表观遗传学 D4Z4在人ES细胞中的特性以确定D4Z4在胚胎发育中的作用 FSHD的临床特点。