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

哺乳动物的剂量补偿是通过雌性X染色体的转录沉默来实现的 性。这一过程被称为“X染色体失活”(XCI)，体现了大量的调控 表观基因组调控中使用的机制，特别是涉及长非编码之间相互作用的机制 RNA(LncRNAs)和染色质修饰物。X-失活中心(XIC)-控制X-连锁区域 沉默的启动、传播和维持--含有大量编码功能的基因 IncRNAs，包括Xist、REPA、TSix和JPX，每一个在XCI过程中都发挥着不同的作用。关键的Xist 当RNA沿着X染色体扩散时，它会启动异染色质的形成。在过去的几年里 在资助期间(2010-2014)，我们的工作帮助确定了Xist RNA招募Polycomb的机制 主要成就包括：(I)发现了装载核素所需的“成核中心”。 Xist-Polycomb络合物在顺式中传播之前；(Ii)将YY1定义为一个基本因素， 将Xist RNA连接到成核中心；(Iii)鉴定多梳结合位点的层级 沿着非活性X；的复合体；以及(Iv)发现了一个全基因组的转录组&gt；9000个转录本， 与PRC2关联。总而言之，这些发现得出了两个重要的结论。第一，目标是 多梳复合体在基因和生物化学上是可以与负载分离的。其次，这两个步骤都需要 核糖核酸。第三，RNA介导的多梳复合体的靶向很可能是表观基因组学的一个总主题 监管。在接下来的五年里，我们将使用XCI作为模型，并扩展对RNA引导的理解 染色质的变化通过寻址：(1)Xist-Polycomb复合体的成核是如何调节的；(2)如何 XCI的传播通过Polycomb站的层级发生；以及(3)lncRNAs如何靶向和加载Polycomb 整个基因组中的复合体。因为许多lncRNA在人类疾病中错误表达， 多梳复合体经常在癌症中异常靶向，这些问题的答案将有助于开发 治疗涉及多梳复合体和lncRNAs的疾病的新方法。

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.