NUCLEAR & CHROMATIN PACKAGING OF MAMMALIAN X CHROMOSOME

描述(改编自《调查者摘要》)：哺乳动物X 染色体构成了一种重要的生物模型和临床模型 兼性异染色质形成的基因组功能 是正常发育的中心，在癌症中被废除。印记的XIST基因 是X失活所必需的，但不编码蛋白质。这个项目 研究了序列特定的相互作用的综合假设 在XIST RNA和染色体之间触发染色质重塑的级联反应 在适当的蜂窝环境中，转变Active X的事件 染色体进入高度浓缩的转录惰性巴尔小体。这个 调查人员发现，稳定的XIST转录本的积累 在结构上与X染色体相关联，本质上“描绘”了 顺式染色体。其他证据支持XIST RNA可以诱导启动 在正常发育环境中染色质失活的可能性。一个中心问题 现在变成了：XIST抄本绘画是如何导致横扫的 整个染色体的凝聚和抑制？这里的关键问题是 关于生化和结构的相互关系 所涉及的更改，尤其是XIST的角色 它的自然背景，在重排的染色体中，或作为常染色体转基因 在正常发育环境之外诱导的。调查人员的创新之处 将精确的分子和生化信息结合在一起的分析方法 直接在染色体结构的背景下对揭示 XIST RNA对染色体的影响。 每个目标都解决了几个具体的假设，作为每个更广泛的目标的一部分 假设如下：1)XIST RNA本身并不直接 抑制转录，但在具有发育能力的细胞中触发 染色体沉默所需的后续变化。2)XIST RNA具有 对常染色体染色质的亲和力降低，导致不完全和 常染色体失活不稳定。3)XIST RNA与其物理相互作用 染色体依赖于染色体DNA和DNA中的特定序列。 XIST的文字记录。4)间期染色体区域内的DNA 表现出更高级别的组织，这在Xi和Xa上是不同的，可能是 由XIST RNA直接用药。在提出的新研究中，有一项是 协同生物信息学搜索高质量的基因组序列基序 对XIST的亲和力，以及产生可诱导的转基因系统，其中 可以很容易地操作Xist表达式来定义它在 启动失活。

DESCRIPTION (Adapted from the Investigator's Abstract): The mammalian X chromosome constitutes a vital biological and clinical model for control of genomic function through formation of facultative heterochromatin, a phenomenon central to normal development and abrogated in cancer. The imprinted XIST gene is required for X inactivation but does not encode a protein. This project investigates the comprehensive hypothesis that sequence-specific interactions between XIST RNA and the chromosome trigger a cascade of chromatin remodeling events that, in the appropriate cellular context, transform an active X chromosome into a highly condensed, transcriptionally inert Barr body. The investigators have shown that an accumulation of stable XIST transcripts structurally associates with the X chromosome, essentially "painting" the chromosome in cis. Other evidence supports that XIST RNA can induce initiation of chromatin inactivation in the normal developmental context. A central issue now becomes: how does painting by XIST transcripts lead to the sweeping condensation and repression of a whole chromosome? Here key questions will be addressed concerning the interrelationship of biochemical and structural changes involved, and the role of XIST in particular, when expressed either in its native context, in rearranged chromosomes, or as an autosomal transgene induced outside normal developmental context. The investigators' innovative analytical approach which couples precise molecular and biochemical information directly in the context of chromosome structure is important for revealing the impact that XIST RNA has on the chromosome. Each aim addresses several specific hypotheses as part of each broader hypothesis, which are as follows: 1) That XIST RNA does not itself directly repress transcription, but in developmentally competent cells triggers subsequent changes required for chromosome silencing. 2) That XIST RNA has compromised affinity for autosomal chromatin which results in incomplete and unstable autosomal inactivation. 3) That XIST RNA's physical interaction with the chromosome depends upon specific sequences both in chromosomal DNA and in the XIST transcript. 4) That DNA within an interphase chromosome territory exhibits higher-order organization, which differs on Xi and Xa, and may be medicated directly by XIST RNA. Among the novel studies proposed is a collaborative bioinformatics search for genomic sequence motifs with high affinity for XIST, and the production of an inducible transgene system in which XIST expression can be easily manipulated to define its precise role in initiating inactivation.