Heterochromatin on the human inactive X chromosome

描述（由申请人提供）：非活性x染色体（Xi）上的基因沉默是通过兼性异染色质的形成实现的，这一特征在随后的细胞分裂中非常稳定并忠实地保留在Xi上。我们已经发现，人类Xi的异染色质被组织成非重叠类型的异染色质，占据确定的基因组间隔。基于特征染色质标记的存在，可以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位点甲基化。这些表观遗传特征的严格空间排列与s期后期复制模式的变化和Xi基因表达谱直接相关。

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.