Nuclear & Chromatin Packaging of Mammalian X Chromosome

描述（由申请人提供）：哺乳动物X染色体是通过兼性异染色质形成的基因组调控的重要生物学和临床模型，这是正常发育的核心现象，在癌症中被废除。正如我们之前的假设，稳定的XIST RNA的积累在结构上与女性的一条X染色体相关，并启动了一个复杂的染色体重塑过程。现在的一个核心问题是：XIST RNA是如何“描绘”它的亲本染色体，并导致整个染色体的全面凝结和永久抑制的？我们的方法允许分子、生化和结构分析彼此直接相关，并将与基因组序列组织的生物信息学相结合。研究包括肿瘤抑制因子BRCA1的作用，最近的发现将其与XIST RNA和剂量补偿的维持联系起来。其他关键问题解决了生化和结构变化与转录抑制的相互关系，当XIST在正常胚胎环境中表达时，以及当发育或染色体环境被操纵时。人类基因组序列分析将有可能揭示参与染色体结构和XIST RNA结合的“垃圾”DNA序列。本研究的意义从阐明发育基因调控和染色体结构的基本机制，到检验具有直接临床意义的创新假设和方法。

DESCRIPTION (provided by applicant): The mammalian X chromosome constitutes a vital biological and clinical model for genome regulation through formation of facultative heterochromatin, a phenomenon central to normal development and abrogated in cancer. As we earlier hypothesized, an accumulation of stable XIST RNA structurally associates with one X chromosome in females and initiates a complex process of chromosome remodeling. A central issue now becomes: how does XIST RNA "paint" its parent chromosome and lead to the sweeping condensation and permanent repression of the whole chromosome? Our approach allows molecular, biochemical and structural analyses in direct relation to one another, and will be coupled with bioinformatics of genomic sequence organization. Studies include the role of the tumor suppressor, BRCA1, which recent findings link to XIST RNA and maintenance of dosage compensation. Other key questions address the interrelationship of biochemical and structural changes with transcriptional repression, when XIST is expressed in normal embryonic context, and when the developmental or chromosomal context is manipulated. Human genome sequence analysis will be pursued with potential to reveal sequences in "junk" DNA involved in chromosome architecture and XIST RNA binding. The significance of this research extends from elucidating fundamental mechanisms of developmental gene regulation and chromosome structure, to testing innovative hypotheses and approaches with direct clinical implications.