骨质疏松是全球化多基因复杂疾病。全基因组关联研究已鉴定出上千个易感位点，但90%以上位于基因组非编码区，使其致病机理难于解析。申请人前期通过表观注释发现近半数易感位点位于超级增强子区，并发现SNP通过超级增强子激活靶基因的调控模式在骨质疏松遗传机制中非常普遍。鉴于超级增强子是新一代热门药物靶点，本项目以此为突破口，利用课题组积累的基因组、三维基因组（Hi-C）、表观组（ChIP-seq、ATAC-seq）和转录组（RNA-seq）的多组学数据，系统分析易感SNP通过超级增强子发挥作用的调控规律，基于超级增强子图谱和染色质三维构象构建骨质疏松的核心转录调控环路（CRC），并结合课题组搭建的高通量实验平台，利用STARR-seq和CRISPR screening进行高通量功能实验验证，准确高效地鉴定影响骨质疏松的关键CRC和核心调控因子。研究结果可为疾病精准医疗和药物开发提供潜在有效靶标。

Osteoporosis is a common complex disease worldwide. Although genome-wide association studies have successfully identified over 1000 susceptibility SNPs for osteoporosis, more than 90% of these SNPs are located in the non-coding regions of genome, and it is difficult to explore their pathogenic mechanisms. In our preliminary study, we have annotated the regulatory role of all the susceptibility SNPs for osteoporosis and found that nearly 50% of those SNPs are located in the super enhancer regions. We also found that it is common for SNPs to activate target genes through super enhancers for osteoporosis. Super enhancers are hypersensitive to drugs and would be a new hot drug target. Based on this, we will systematically analyze the super enhancer regulatory modes for susceptibility SNPs by using our multiple-omics data, including genomics, 3D genomics (Hi-C), epigenomics (ChIP-seq and ATAC-seq), and transcriptomic (RNA-seq) data. We will construct core transcriptional regulatory circuitries (CRC) based on super enhancer landscape and chromotin conformation for osteoporosis. Then, we will conduct high-throughput functional experiments, such as STARR-seq and CRISPR screening by using our platform, to systematically validate the regulatory roles and identify key CRC and regulatory factors. The completion of this project will provide potential effective targets for individualized diagnosis and drug development.