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

描述(申请人提供)：染色体组织和染色质结构在基因表达调控中起主要作用，在发育、分化和癌症中具有重要功能。我们的长期目标是通过开发和应用概率方法来从全基因组表达谱和其他基因组数据中识别受调控的染色体结构域(CDS)-共调控基因的物理簇，以及控制它们的机制，从而了解它们在基因组范围内对基因调控的影响。这种对CDS的全基因组研究可以提供新兴的染色质结构和调控领域与这种结构被认为指导的转录读出之间缺失的联系。由于染色质及其修饰在一系列人类癌症中有牵连和靶点，这种对其转录的影响可能具有重要的诊断和治疗意义。我们的具体目标是：1.创建一个全面的染色体结构域图谱。我们将开发从基因表达谱和其他基因组数据中识别CD的概率方法，以及相应的统计框架，以表征不同生物条件下CD的功能和行为。2.确定调控CDS的候选分子机制。我们将构建详细的CD调控机制模型，整合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。这些将提出关于参与CD调控的序列元件、调节蛋白和表观遗传学特征的特定的可检验的假说。3.阐明染色体结构域的进化史。如果CD具有重要的功能，我们预计它们的部分组织将在有机体中保留。我们将开发一个比较基因组框架来识别进化保守的CD和在CD边界内或在CD边界处保守的序列元件，并利用这些结果来表征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。染色体异常是癌细胞的一个标志。我们将开发一个染色体异常的概率模型，整合表达和比较基因组杂交(CGH)数据，以区分CDS的错误调节和总的染色体变化，为区域调节在癌症中的作用提供一个统一的模型。

DESCRIPTION (provided by applicant): 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 li nk 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.