Variation, functions, and dynamics of human subtelomeres

人类亚端粒的变异、功能和动态

• 批准号: 7319137
• 负责人: BARBARA J. TRASK
• 金额: $ 51.54万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319137
• 关键词: 10q; Actins; Affect; Aging; Alleles; Attention; Biological; Biological Assay; Biology; Cell Line; Cell hybridization; Cells; Characteristics; Chromatin; Chromatin Structure; Chromosomes; Climate; Complement; Condition; Contracts; Counseling; Custom; Cytoskeleton; D4Z4; DNA; DNA Methylation; Diagnosis; Dimensions; Disease; Distal; Doctor of Philosophy; Epigenetic Process; Etiology; FAT gene; Family; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Recombination; Genome; Genomics; Goals; Heterochromatin; Histones; Human; Human Genome; Hybrid Cells; Inborn Genetic Diseases; Individual; Inherited; Lamin Type A; Lead; Link; Location; Malignant Neoplasms; Methods; Modification; Muscle function; Muscular Dystrophies; Myoblasts; Nature; Nuclear; Nuclear Matrix; Numbers; Patients; Physical condensation; Play; Proteins; Recurrence; Regulation; Research; Research Personnel; Resolution; Resources; Risk; Role; Short Tandem Repeat; Signal Transduction; Structure; Surveys; Tandem Repeat Sequences; Testing; Variant; WASP protein; Work; base; demethylation; experience; extracellular; interest; new technology; novel; paralogous gene; programs; response; telomere; tool

DESCRIPTION (provided by applicant): We propose to generate the first high-resolution, comprehensive view of the epigenetic landscape of subtelomeres, the most variable and recombination-prone regions of the human genome. Subtelomeric genes vary markedly in copy number, location, and sequence context among individuals. To fully understand the biological significance of these fast-evolving regions, we will characterize the epigenetic context in which subtelomeric genes operate. In addition to their genomic plasticity, these regions are likely to have unusual chromatin structure due to their proximity to telomeric heterochromatin and abundance of other tandem repeats. We will survey the epigenetic state of many chromosomal ends, but give more attention to subtelomeres with highest relevance to human function and disease. One such region is 4qter, where recurrent contraction of a tandem array, in the context of just one of two structurally variant subtelomeric alleles (4qA), leads to facio-scapulo-humeral dystrophy (FSHD), the third most common inherited muscular dystrophy. This deletion is believed to induce epigenetic changes that cause inappropriate gene expression in 4q or elsewhere, but it is not known how this occurs or what genes are affected. We aim to identify the genetic and epigenetic features of normal and FSHD-causing 4qA alleles in order to provide a link between the 4q deletion and aberrant muscle function. This work should lead to better diagnosis and counseling of recurrence risk for FSHD patients. We will also focus on regions surrounding WASH genes, which exist in grossly different allelic and paralogous contexts in human subtelomeres. We recently discovered that WASH genes encode a highly conserved, widely expressed, yet previously unrecognized new subfamily of WASP proteins, which reorganize the actin cytoskeleton in response to extracellular signals. To accomplish our goals, we will characterize in detail genomic differences among 4qter alleles and among selected chromosomes carrying WASH, as these regions have very limited representation in the current human genome assembly. For epigenetic profiling, we will develop a microarray covering sequences in and near subtelomeres, regions lacking from other arrays. We will use these arrays to analyze subtelomeres in various cells for chromatin modifications characteristic of repressed and active chromatin. In parallel, we will use FISH to analyze larger-scale epigenetic features of specific WASH or 4q copies, such as nuclear location, chromatin condensation, and matrix association. Finally, we will apply tools capable of distinguishing SNPs and paralogous sequence variants (PSVs) to directly relate epigenetic characteristics with transcriptional activity of specific copies. This research will illuminate the significance of subtelomeric genomics and epigenetics in normal phenotypic variation among humans, as well as in inherited disorders, cancer, and aging.

描述（由申请人提供）：我们提议生成第一个高分辨率，全面的观点，即亚端子的表观遗传景观，这是人类基因组的最大和重组区域。亚telomeric基因在个体之间的拷贝数，位置和序列上下文中明显变化。为了充分理解这些快速发展区域的生物学意义，我们将表征亚电位基因运行的表观遗传环境。除了它们的基因组可塑性外，这些区域还可能具有异常的染色质结构，因为它们靠近端粒异染色质和其他串联重复序列的丰度。我们将调查许多染色体末端的表观遗传状态，但要更多地关注与人类功能和疾病最相关的亚tel虫。一个这样的区域是4QTER，其中串联阵列的反复收缩仅在两个结构上变体的子端粒等位基因（4QA）的背景下，导致facio-scapulo-Humeral-Humeral Dromhytrophy（FSHD），这是第三个最常见的遗传性肌肉营​​养不良症。据信这种缺失会诱导在4Q或其他地方引起不适当基因表达的表观遗传学变化，但尚不清楚这种情况是如何发生或受到哪些基因的影响。我们旨在确定正常和FSHD引起的4QA等位基因的遗传和表观遗传特征，以提供4Q缺失和异常肌肉功能之间的联系。这项工作应导致更好的诊断和咨询FSHD患者的复发风险。我们还将重点关注清洗基因周围的区域，这些区域存在于人类亚tele虫中的严重不同和旁系背景下。我们最近发现，WASH基因编码了一种高度保守的，广泛表达但先前未识别的WASP蛋白亚科，该基因对细胞外信号的响应重组了肌动蛋白细胞骨架。为了实现我们的目标，我们将在4QETER等位基因和携带洗涤的选定染色体之间进行详细的基因组差异表征，因为这些区域在当前的人类基因组组装中的表示非常有限。对于表观遗传分析，我们将开发一个微阵列，覆盖了亚电域内外的序列，其他阵列缺乏区域。我们将使用这些阵列来分析各种细胞中的亚近样组，以进行抑制和活性染色质的染色质修饰。同时，我们将使用鱼类来分析特定洗涤或4Q拷贝的大规模表观遗传特征，例如核位置，染色质凝结和基质关联。最后，我们将应用能够区分SNP和寄生态序列变体（PSV）的工具将表观遗传特性与特定拷贝的转录活性联系起来。这项研究将阐明亚端细胞基因组学和表观遗传学在人类以及遗传性疾病，癌症和衰老中的正常表型变异中的重要性。