Alu转座调控因子的全基因组筛选及其分子机制研究

Alu占据大约11%的人体基因组，是目前人体内最活跃的转座子。Alu转座能够改变人体基因，造成个体内和个体间基因组差异。研究表明Alu转座在哺乳动物胚胎和神经发育过程中发挥重要作用，同时Alu转座失调与人体多种疾病发生有关。然而，哪些基因参与到Alu转座调控目前尚未得到系统研究，并且Alu对人体基因表达的影响至今没有被完全理解。.本项目将在前期工作的基础上，拟利用CRISPR-Cas9基因筛选技术在人细胞系中、全基因组范围内筛选与Alu转座调控相关的基因。依据筛选结果，项目将探明人体调控Alu转座的通路机制，以及Alu对人体基因表达的影响。项目也将通过研究与疾病相关的Alu调控因子来阐释Alu转座调控与人体健康之间的联系。.本项目通过全基因组筛选，预期将会揭示人体内调控Alu转座的新通路，并且为研究Alu转座调控机制以及Alu转座对基因表达和人体健康的影响提供宝贵资源。

Alu, the most active transposon in humans, occupies 11% of the genome. Alu can mobilize within the human genome, and generates inter- and intra- individual genetic variation. Recent studies show that Alu regulation plays important roles during mammalian embryogenesis and neurogenesis, while abnormal Alu activities were detected in many human disorders. However, how Alu activity is controlled and the exact function of Alus in host gene regulation are not completely understood. Here, we propose to leverage our CRISPR-Cas9 screening strategies in human cell lines to provide a genome-wide survey of genes involved in the control of Alu retrotransposition. By following up on the screen hits, we will study the detailed mechanism how Alu retrotransposition is controlled as well as the influence of Alus on human gene expression programs. We will also focus on the development- and disease- related screen hits to investigate the relations between Alu regulation and human health. Together, these studies are expected to uncover novel pathways that control Alu life-cycle and provide a rich resource to study the mechanism of Alu retrotransposition regulation, as well as the impact of Alu activities on gene expression and human health.