Mobile element mutagenesis as a driver of human cancers

项目摘要。 人类LINE-1(L1)元件是自主反转录转座子，能继续产生新的 人类基因组中的“后代”L1插入。直到最近，L1元素还被认为主要是被动员起来的 在生殖系中，然后在整个成年期的体细胞中保持沉默。然而，最近的几份报告显示， 研究表明，L1元素至少在一些成人的躯体组织中是活跃的，包括大脑和上皮组织 躯体肿瘤。这些观察结果导致了L1可能在启动人类 通过在体细胞中突变特定的肿瘤抑制基因和癌基因而导致的癌症。在这三个目标中 建议，我们将进一步探索这一假说，重点研究表达，调节和 动员产生新的L1插入的全长L1源元件。在具体目标1中，我们将 生成全长、人类特定的L1(FL-L1Hs)源元素的全面资源，这些资源将 在整个方案中使用(目标1-3)来研究L1动员在人体组织和肿瘤中的作用。在……里面 具体目标2，我们将检测FL-L1Hs元件的表达和调控，这些元件可以逃避体细胞 并将研究这些分子设法做到这一点的机制(S)。最后，具体地说 目的3，检测FL-L1Hs分子的动员能力。结合在中生成的数据 目标1和2，这些数据将使我们更好地理解表达、调节和动员 突变人类基因组的FL-L1Hs元件。三个目标的圆满实现 这项研究将改变我们对移动元素如何影响包括癌症在内的人类疾病的理解。

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.