Mobile element mutagenesis as a driver of human cancers

移动元件突变是人类癌症的驱动因素

• 批准号: 10517586
• 负责人: Scott E Devine
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517586
• 关键词: Adult; Brain; Colorectal; Complement; DNA Insertion Elements; Data; Data Collection; Elements; Epithelial; Genome; Goals; Human; Human Genome; L1 Elements; Length; Lung; Malignant Neoplasms; Mediating; Methods; Methylation; Mission; Mobile Genetic Elements; Mutagenesis; Mutate; National Cancer Institute; Normal tissue morphology; Oncogenes; Pancreas; Play; Regulation; Reporting; Repression; Resources; Retrotransposon; Role; Sampling; Somatic Cell; Source; Suggestion; The Cancer Genome Atlas; Tissues; Tumor Suppressor Genes; Tumor Tissue; Work; base; human disease; human tissue; novel; offspring; tumor; tumorigenesis

Project Summary. Human LINE-1 (L1) elements are autonomous retrotransposons that continue to produce new “offspring” L1 insertions in human genomes. Until recently, L1 elements were thought to be mobilized primarily in the germline and then silenced in somatic cells throughout adulthood. However, several recent reports have shown that L1 elements are active in at least some adult somatic tissues, including the brain and epithelial somatic tumors. These observations have led to the suggestion that L1 might play a role in initiating human cancers by mutating specific tumor suppressor genes and oncogenes in somatic cells. In the three aims of this proposal, we will further explore this hypothesis with an emphasis on studying the expression, regulation, and mobilization of the full-length L1 source elements that generate new L1 insertions. In Specific Aim 1, we will generate a comprehensive resource of full-length, human-specific L1 (FL-L1Hs) source elements that will be used throughout this proposal (Aims 1-3) to study the role of L1 mobilization in human tissues and tumors. In Specific Aim 2, we will examine the expression and regulation of FL-L1Hs elements that can evade somatic repression and will study the mechanism(s) whereby these elements manage to do this. Finally, in Specific Aim 3, we will examine the mobilization capacities of FL-L1Hs elements. Combined with the data generated in Aims 1 and 2, these data will allow us to better understand the expression, regulation, and mobilization of the FL-L1Hs elements that mutagenize the human genome. The successful completion of the three Aims of this study will transform our understanding of how mobile elements impact human diseases, including cancers.

项目摘要。 人类 LINE-1 (L1) 元件是自主逆转录转座子，能够持续产生新的 直到最近，L1 元件还被认为主要是被动员起来的。 然而，最近的一些报告表明， 研究表明，L1 元件至少在一些成人体细胞组织中具有活性，包括大脑和上皮细胞 这些观察结果表明 L1 可能在人类肿瘤的启动过程中发挥作用。 通过突变体细胞中的特定肿瘤抑制基因和癌基因来预防癌症。 提案中，我们将进一步探讨这一假设，重点是研究表达、调控和 在特定目标 1 中，我们将动员产生新的 L1 插入的全长 L1 源元素。 生成完整的、人类特定的 L1 (FL-L1Hs) 源元素的综合资源，这些元素将 本提案（目标 1-3）中使用该方法来研究 L1 动员在人体组织和肿瘤中的作用。 具体目标2，我们将检查可以逃避体细胞的FL-L1Hs元件的表达和调节 最后，具体来说，我们将研究这些因素实现这一目标的机制。 目标 3，我们将结合 中生成的数据检查 FL-L1Hs 元素的动员能力。 目标 1 和 2，这些数据将使我们能够更好地了解 诱变人类基因组的 FL-L1Hs 元件成功完成了本次的三个目标。 研究将改变我们对移动元素如何影响人类疾病（包括癌症）的理解。