Genome-wide analysis of regulated chromosomal domains: From mechanisms to cancer

染色体组织和染色质结构在基因表达调控中起着重要作用， 在发育、分化和癌症中具有重要作用。我们的长期目标是了解他们的 开发和应用识别概率方法对基因调控的全基因组影响 受调控的染色体结构域(CDS)--共调控基因的物理簇，以及 从全基因组表达谱和其他基因组学数据中控制它们。这样的全基因组研究 可以弥补染色质结构和调控这一新兴领域与 被认为是这个结构指导的转录读出。因为染色质及其修饰是 在一系列人类癌症中有牵连和靶点，这种与其转录I效应的联系可能具有 重要的诊断和治疗意义。我们的具体目标是： 1.创建一张全面的染色体结构域地图。我们将开发概率方法来解决 从基因表达谱和其他基因组数据中识别CD，以及随附的统计数据 用于描述不同生物条件下镉的功能和行为的框架。 2.确定调控CDS的候选分子机制。我们将构建详细的机械结构 CD调控模型整合了不同类型的基因组数据，包括基因表达， DMA序列和组蛋白修饰数据。这些将提出具体的可测试的假设，关于 参与Cd调控的序列元件、调节蛋白和表观遗传学特征。 3.阐明染色体结构域的进化史。如果CD发挥着重要的作用，我们 希望他们的组织的一部分在有机体中是保守的。我们将开发一种比较基因组 用于识别进化上保守的CDs和序列元件的框架 Cd边界，并使用这些结果来表征Cd在基因组进化中的作用。 4.了解染色体结构域在癌症中的作用。染色体异常是一种 癌细胞。我们将开发一个整合了表达的染色体畸变的概率模型 和比较基因组杂交(CGH)数据来区分CDS的错误调控和总的 染色体的变化，为区域调控在癌症中的作用提出了一个统一的模型。

Chromosomal organization and chromatin structure play a major role in the regulation of gene expression, with important functions in development, differentiation, and cancer. Our long-term goal is to understand their genome-wide effect on gene regulation by developing and applying probabilistic methods for identifying regulated chromosomal domains (CDs) - physical clusters of co-regulated genes, and the mechanisms that control them, from genome-wide expression profiles and other genomics data. Such a genome-wide study of CDs can provide the missing link between the emerging field of chromatin structure and regulation and the transcriptional readout that this struct ure is thought to direct. As chromatin and its modifications are implicated and targeted in a rang e of human cancers, this link to their transcriptiona I effect may have important diagnostic and thera peutic implications. Our specific aims are to: 1. Create a comprehensive map of chromosomal domains. We will develop probabilistic methods for identifying CDs from gene expression profiles and other genomics data, and an accompanying statistical framework for characterizing the function and behavior of CDs across different biological conditions. 2. Identify candidate molecular mechanisms that regulate CDs. We will construct detailed mechanistic models of CD regulation that integrate heterogeneous types of genomic data, including gene expression, DMA sequence, and histone modification data. These will suggest specific testable hypotheses regarding the sequence elements, regulatory proteins, and epigenetic features that are involved in CD regulation. 3. Elucidate the evolutionary history of chromosomal domains. If CDs serve an important function, we expect part of their organization to be conserved across organisms. We will develop a comparative genomic framework to identify evolutionary conserved CDs and sequence elements that are conserved within or at CD boundaries, and use these results to characterize the role of CDs in genome evolution. 4. Understand the role of chromosomal domains in cancer. Chromosomal aberrations are a hallmark of cancer cells. We will develop a probabilistic model of chromosome aberrations that integrates expression and comparative genomic hybridization (CGH) data to distinguish between mis-regulation of CDs and gross chromosomal changes, suggesting a unified model for the role of regional regulation in cancer.