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

剖析转座元件在人类癌症中的顺式调控作用

• 批准号: 10231204
• 负责人: Yanxiao Zhang
• 金额: $ 11.37万
• 依托单位: LUDWIG INSTITUTE FOR CANCER RES LTD
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231204
• 关键词: Advisory Committees; Aging; Architecture; Award; Biological Assay; CRISPR screen; Cancer Cell Growth; Cancer Etiology; Cancer cell line; ChIP-seq; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Sequence Alteration; DNA Transposable Elements; Data; Development; Distal; Encyclopedias; Endogenous Retroviruses; Enhancers; Epigenetic Process; Eukaryotic Cell; Family; Foundations; Future; Gene Expression; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Genomics; Genotype; Genotype-Tissue Expression Project; Goals; Hi-C; Higher Order Chromatin Structure; Human; Human Genome; Iceberg; In Vitro; Institutes; Insulator Elements; Jumping Genes; Lead; Light; Malignant Neoplasms; Mentors; Molecular; Mus; Mutation; Oncogene Activation; Oncogene Deregulation; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Phase; Positioning Attribute; Primary Neoplasm; Property; Regulation; Regulator Genes; Regulatory Element; Reporter; Repression; Research; Research Personnel; Role; Series; Somatic Cell; Suppressor-Effector T-Lymphocytes; Technology; Testing; The Cancer Genome Atlas; Tissues; Training; Tumor Suppressor Genes; Tumor stage; Tumor-Suppressor Gene Inactivation; Work; Xenograft Model; base; cancer cell; cancer type; career; cell growth; chromatin remodeling; cohesin; experimental study; human disease; insight; interdisciplinary approach; neoplastic cell; overexpression; overexpression analysis; post-doctoral training; promoter; transcriptome sequencing; tumorigenesis

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.

项目总结/摘要 近一半的人类基因组由转座因子（TE）组成，也称为转座因子。“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揭示 关于TEs的多方面功能，但对它们对人类疾病的影响的质疑仍然缺乏。 大多数TE在体细胞组织中被抑制，但一些TE家族在体细胞组织中被一致地重新激活。 癌已经揭示，TE通过主动转座和通过免疫调节促进肿瘤发生。 提供替代启动子以驱动癌基因表达。然而，这些机制可能代表了 冰山一角张博士和其他人最近的工作表明，TE可以改变高级染色质 结构（绝缘子作用）和增强附近基因的表达（增强子作用）。这些发现表明 令人感兴趣的可能性是，癌症中TE的重新激活可能类似地重塑高级染色质， 结构并引起癌基因和肿瘤抑制基因错误调节，从而促进肿瘤发生。这 该提案旨在通过利用 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）。博士 Zhang将采用基因组分析和报告基因分析来确定增强子和绝缘子的特性。 癌细胞系中的TE（Aim 1）。随后，张博士将通过计算预测和实验 验证TE作为顺式调节元件对附近癌基因和肿瘤抑制基因的功能影响 基因和癌细胞生长（Aim 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（Aim 3）。总的来说，这项提案的结果将揭示新的监管作用， TE在人类疾病中的作用，并扩大我们对导致基因失调的机制的理解， 肿瘤发生 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 人类衰老和癌症的表观遗传失调。在K99阶段，他将继续接受 计算和实验培训，从他的博士后导师任博士和他的顾问委员会在 路德维希研究所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R 00阶段向独立研究者过渡，并为 他未来的职业生涯。