真核生物基因组转录因子聚集区域的演化规律及其与肿瘤的关系

Recent studies have revealed that transcription factor binding is highly clustered in eukaryotes, based on this phenomenon, we developed a set of algorithm to identify transcription factor clustered regions (TFCR).We found that TFCR play a central role in regulation, which are also associated with many human disease. Further study show that cross-species analysis of TFCR is an important way to reveal the evolution of transcriptional regulation mechanism. Here, we will study the TFCR systematically from the perspective of genomic evolution and further explore its relation with tumor. We select yeast, worm, fruit fly, zebra fish, mouse, macaques, chimpanzee and human as the research object. We will identify TFCR in each species, compare the difference of them, and establish TFCR regulating model for each of them. Finally, we will focus on the conservative TFCR and study its important role in tumor, the conservative TFCR could be tumor targets. Our work will reveal the reason why transcription factor binding is highly clustered, provide genome evidence for understanding the evolution of transcriptional regulation mechanism. What’s more, this project may provide a scientific basis for discovering new tumor targets.

申请人前期工作发现转录因子在真核生物基因组中聚集分布，开发了识别转录因子聚集区域（TFCR）的算法，并发现TFCR具有重要的调控功能，与肿瘤等重大疾病有密切联系。随着研究的深入，我们发现跨物种TFCR比较研究是揭示转录调控机制演化规律的重要途径。本课题拟从基因组演化的视角来系统研究TFCR的调控规律，并挖掘其与肿瘤的关系。我们选取酵母、线虫、果蝇、斑马鱼、小鼠、猕猴、黑猩猩以及人类八个物种作为研究对象，首先分别在各物种中识别TFCR并建立TFCR调控基因表达模型，然后比较TFCR在物种之间的演化规律，最后研究物种之间保守的TFCR及其在肿瘤发生发展中所起的重要调控作用。本课题将揭示转录因子聚集分布的成因，为深入理解转录调控机制的演化规律提供证据。预期成果将有助于揭示生物性状演化的表观遗传基础，推动TFCR研究的临床应用，为开发新的基于非编码区的肿瘤诊断标志物提供科学依据。

本课题从基因组演化的视角来系统研究TFCR的调控规律，并挖掘其与肿瘤的关系。我们选取酵母、线虫、果蝇、斑马鱼、小鼠、猕猴、黑猩猩以及人类八个物种作为研究对象，首先分别在各物种中识别TFCR并建立TFCR调控基因表达模型，然后比较TFCR在物种之间的演化规律，最后研究物种之间保守的TFCR及其在肿瘤发生发展中所起的重要调控作用。在本项目的支持下，负责人重点研究了真核生物基因组转录因子聚集区间的演化规律及其与肿瘤的关系，具体来说：第一，总结相关数据并建立数据库；第二，建立了各物种TFCR的调控模型；第三，刻画了TFCR的演化规律及其影响因素；第四，提出了基于转录因子调控网络预测方法；第五，表征影响TFCR特异性的表观遗传因素并构建相关算法。本课题揭示了转录因子聚集分布的成因，为深入理解转录调控机制的演化规律提供证据，有助于揭示生物性状演化的表观遗传基础，推动TFCR研究的临床应用，为开发新的基于非编码区的肿瘤诊断标志物提供科学依据。