Dissecting the cis-regulatory roles of transposable elements in human cancers

项目摘要/摘要 近一半的人类基因组由转座元件(TES)组成，又名TES。“跳跃基因”； 然而，令人惊讶的是，我们对它们知之甚少。基因组技术的兴起已经开始显现 关于TES的多方面功能，但关于其对人类疾病的影响的询问仍然缺乏。 大多数TE在体细胞组织中被抑制，但一些TE家族在体内持续重新激活 癌症。已有研究表明，TES通过主动转座和 提供替代启动子来驱动癌基因的表达。但是，这些机制可能代表 冰山一角。张博士等人最近的研究表明，TES可以改变高阶染色质 结构(绝缘体作用)和增强邻近基因的表达(增强子作用)。这些发现表明 耐人寻味的可能性是，癌症中TES的重新激活可能同样会重塑高阶染色质 结构和原因癌基因和抑癌基因调控不当，从而促进肿瘤的发生。这 该提案旨在全面描述癌症患者重新激活的TES的情况 公共联盟数据，包括癌症基因组图谱(TCGA)和癌细胞系百科全书(CCLE)。Dr。 张将使用基因组分析和报告分析来确定增强剂和绝缘体的性质 肿瘤细胞系中的TES(目标1)。随后，张博士将通过计算预测和实验 验证TES作为顺式调控元件对邻近癌基因和抑癌基因的功能影响 基因与癌细胞生长(目标2)。最后，张博士将研究导致TE过度的机制。 在癌细胞中的表达(目标3)。总体而言，这项提案的结果将揭示出新的监管角色 TES在人类疾病中的作用，并扩大我们对导致基因放松管制和 致癌作用。 张博士的职业目标是领导一个独立的研究小组，致力于了解 人类衰老和癌症中的表观遗传失调。在K99阶段，他将继续接受 他的博士后导师任博士和他的顾问委员会提供的计算和实验培训 路德维希学院和加州大学圣地亚哥分校。在K99阶段获得的严格指导支持和结果将 促进张博士在R00阶段向独立的研究员过渡，并为 他未来的职业生涯。

Project Summary/Abstract Nearly one half of the human genome consists of transposable elements (TEs), a.k.a. “jumping genes”; however, we know surprisingly very little about them. The rise of genomic technologies has begun to shed light on the multi-faceted functions of TEs, but interrogations of their impact on human diseases are still lacking. The majority of TEs are suppressed in somatic tissues, but some TE families are consistently re-activated in cancer. It has been revealed that TEs contribute to tumorigenesis both through active transposition and by providing alternative promoters to drive oncogene expression. However, these mechanisms may represent the tip of an iceberg. Recent works from Dr. Zhang and others show that TEs can alter higher-order chromatin architecture (insulator role) and enhance expression of nearby genes (enhancer role). These findings suggest the intriguing possibility that re-activation of TEs in cancer may similarly remodel higher-order chromatin structure and cause oncogene and tumor suppressor mis-regulation, thus contributing to tumorigenesis. This proposal aims to comprehensively characterize the landscape of re-activated TEs in cancer by leveraging public consortia data, including the cancer genome atlas (TCGA) and cancer cell line encyclopedia (CCLE). Dr. Zhang will employ genomic assays and reporter assays to determine the enhancer and insulator properties of TEs in cancer cell lines (Aim 1). Subsequently, Dr. Zhang will computationally predict and experimentally validate functional impact of TEs as cis-regulatory elements on the nearby oncogenes and tumor suppressor genes and cancer cell growth (Aim 2). Finally, Dr. Zhang will investigate the mechanisms causing TE over- expression in cancer cells (Aim 3). Overall, the results from this proposal will reveal new regulatory roles of TEs in human diseases, and expand our understanding of the mechanisms leading to gene deregulation and oncogenesis. Dr. Zhang's career goal is to lead an independent research group devoted to understanding the epigenetic dysregulation in human aging and cancer. During the K99 phase, he will continue to receive computational and experimental training from his postdoctoral mentor Dr. Ren and his advisory committee at Ludwig Institute and UC San Diego. The rigorous mentored support and results obtained in the K99 phase will facilitate Dr. Zhang's transition to independence as an investigator in the R00 phase, and lay the foundation for his future career.