Polycomb complexes targeted to specific loci by long noncoding RNA cofactors.

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30 文本行。 哺乳动物中的剂量补偿通过雌性中一条X染色体的转录沉默发生 性这一过程被称为“X染色体失活”（XCI），它使大量的调节性染色体失活。 表观基因组调控中使用的机制，特别是那些涉及长非编码 RNA（lncRNA）和染色质修饰剂。X-失活中心（Xic）-X连锁区域，控制 沉默的启动、传播和维持包含大量编码功能性 lncRNA，包括Xist、RepA、Tsix和Jpx，它们中的每一个在XCI期间起着不同的作用。关键的Xist 当RNA沿X染色体沿着扩散时，RNA启动异染色质的形成。在过去 在资助期间（2010-2014年），我们的工作帮助定义了Xist RNA招募Polycomb的机制 配合物X.主要成果包括：（i）发现了一个“成核中心”， Xist-Polycomb复合物在它们顺式繁殖之前;（ii）将YY 1定义为必需因子， 将Xist RNA拴系到成核中心;（iii）识别Polycomb扩散的结合位点的层次结构 沿着无活性的X复合;和（iv）揭示> 9，000个转录物的全基因组转录组， 联系PRC 2总之，这些发现导致了两个过度的结论。第一，针对 多梳复合物在遗传和生物化学上可与负载分离。其次，这两个步骤都需要 核糖核酸第三，RNA介导的Polycomb复合物的靶向可能是表观基因组学中的一般主题。 调控在接下来的五年里，我们将使用XCI作为模型，并扩展对RNA引导的 染色质的变化通过解决：（1）如何调节Xist-Polycomb复合物的成核;（2）如何 XCI的扩散通过Polycomb站的层级发生;以及（3）lncRNA如何靶向和加载Polycomb 在整个基因组中。因为许多lncRNA在人类疾病中错误表达， Polycomb复合物通常在癌症中异常靶向，这些问题的答案将有助于开发 治疗涉及Polycomb复合物和lncRNA的疾病的新方法。

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Dosage compensation in the mammal occurs by transcriptional silencing of one X-chromosome in the female sex. Known as “X-chromosome inactivation” (XCI), this process exemplifies the large number of regulatory mechanisms used in epigenomic regulation, particularly those involving interactions between long noncoding RNAs (lncRNAs) and chromatin modifiers. The X-inactivation center (Xic) — the X-linked region that controls the initiation, spread, and maintenance of silencing — harbors a large number of genes encoding functional lncRNAs, including Xist, RepA, Tsix, and Jpx, each of which plays a distinct role during XCI. The crucial Xist RNA initiates formation of heterochromatin as the RNA spreads along the X-chromosome. During the last funding period (2010-2014), our work has helped define mechanisms by which Xist RNA recruits Polycomb complexes to the X. Major achievements include: (i) discovering a “nucleation center” required for loading of Xist-Polycomb complexes before they are propagated in cis; (ii) defining YY1 as an essential factor that tethers Xist RNA to the nucleation center; (iii) identifying a hierarchy of binding sites for spreading of Polycomb complexes along the inactive X; and (iv) uncovering a genomewide transcriptome of >9,000 transcripts that associate with PRC2. Together, these findings lead to two over-arching conclusions. First, targeting of Polycomb complexes is genetically and biochemically separable from loading. Second, both steps require RNA. Third, RNA-mediated targeting of Polycomb complexes is likely to be a general theme in epigenomic regulation. Over the next five years, we will use XCI as a model and extend understanding of RNA-guided chromatin change by addressing: (1) How nucleation of the Xist-Polycomb complex is regulated; (2) How spreading of XCI occurs via a hierarchy of Polycomb stations; and (3) How lncRNAs target and load Polycomb complexes throughout the genome. Because many lncRNAs are misexpressed in human disease and Polycomb complexes are often aberrantly targeted in cancers, answers to these questions will help develop novel methodologies to treat diseases in which Polycomb complexes and lncRNAs are implicated.