Heterochromatin on the human inactive X chromosome

人类失活 X 染色体上的异染色质

• 批准号: 7342441
• 负责人: Brian P. Chadwick
• 金额: $ 27.74万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342441
• 关键词: 1 year old; Appearance; Attention; Biological Assay; Cell division; Cells; Characteristics; Chromatin; Chromosomes; Class; Code; Complex; Custom; DNA; Data; Depth; Development; Distal; Elements; Ensure; Epigenetic Process; Euchromatin; Female; Fluorescent in Situ Hybridization; Functional RNA; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Silencing; Genome; Genomics; Heterochromatin; Histone H3; Histones; Human; Human Development; Instruction; Interphase; Investigation; Length; Link; Lysine; Maintenance; Mammals; Maps; Mediating; Metaphase; Modeling; Modification; Monitor; Nature; Pattern; Phase; Polymerase Chain Reaction; Positioning Attribute; Process; Proteins; RNA; RNA Interference; Relative (related person); Research Design; Resolution; Role; Sex Chromatin; Somatic Cell; Specific qualifier value; Testing; Thinking; Time; Variant; X Chromosome; X Inactivation; base; chromatin immunoprecipitation; chromatin protein; concept; dosage; immunocytochemistry; insight; research study; sex

DESCRIPTION (provided by applicant): Gene silencing at the inactive X-chromosome (Xi) is achieved through the formation of facultative heterochromatin, a feature that is remarkably stable and faithfully retained at the Xi throughout subsequent cell divisions. We have found that heterochromatin of the human Xi is organized into non-overlapping types of heterochromatin that occupy defined genomic intervals. Two distinct heterochromatin types can be defined based upon the presence of characteristic chromatin markers: I,macroH2A and XIST RNA; II, HP1 and histone H3 methylated at lysine-9. The strict spatial arrangement of these epigenetic features correlates directly with variation in the pattern of replication in late S-phase and with the Xi gene expression profile. These data provide the framework for testing interrelationships between the epigenetic and epiphenotypic features of Xi heterochromatin. The experiments described here have two specific aims: (i) To precisely define the proximal and distal boundaries of the major Xi Type-I territory; and (ii) To investigate the role of the protein components of each territory in maintaining and/or constraining the heterochromatin types along the Xi. These experiments will generate a detailed map across the specified interval, allowing us to determine the precise organization of epigenetic markers relative both to one another and to the Xi epiphenotypes, thus acting as a model for the entire Xi. By selectively removing specific heterochromatin markers, we will be able to monitor the effects on all features of the Xi, allowing us to determine the functional significance of the epigenetic components in maintaining Xi heterochromatin. Not only will these data substantially advance our understanding of X-inactivation, they will also provide valuable insight generally into the regulation of gene expression and the inheritance of defined chromatin states, a critically important aspect of all human development and cellular differentiation.

描述（由申请人提供）：通过形成兼性异染色质，在无效的X染色体（XI）处进行基因沉默，这一特征非常稳定，并且在随后的细胞分裂中非常稳定并忠实地保留在XI上。我们发现，人XI的异染色质被组织成占据定义的基因组间隔的异染色质的非重叠类型。可以根据特征性染色质标记的存在来定义两种不同的异染色质类型：i，macroh2a和Xist RNA； II，HP1和组蛋白H3在赖氨酸9处甲基化。这些表观遗传特征的严格空间排列与S期晚期复制模式和XI基因表达谱直接相关。 这些数据为测试XI异染色质的表观遗传和表观型特征之间的相互关系提供了一个框架。 此处描述的实验具有两个具体的目的：（i）精确定义了主要XI型I型领域的近端和远端边界； （ii）研究每个区域的蛋白质成分在维持和/或沿XI沿杂染色质类型构成的作用。 这些实验将在指定的间隔上生成详细的图，从而使我们能够确定相对的表观遗传标志物的精确组织，并在XI表观型中确定，从而充当整个XI的模型。通过选择性去除特定的异染色质标记，我们将能够监视XI所有特征的影响，从而使我们能够确定表观遗传成分在维持XI异染色质方面的功能意义。这些数据不仅可以大大提高我们对X灭活的理解，而且还将普遍提供有价值的洞察力，以调节基因表达和定义的染色质状态的遗传，这是所有人类发育和细胞分化的至关重要的方面。