骨质疏松症是一种典型的多基因复杂疾病。90%以上的骨质疏松症易感位点位于基因组非编码区，给进一步解析其遗传调控机制带来了挑战。1p13.2是一个重复报道的骨质疏松症易感热点区，然而具体的遗传调控机制未知。近期Cell杂志报道启动子区易感SNP也能通过增强子调控远端靶基因，这种特殊的启动子被命名为双功能启动子（“Epromoter”）。申请人前期联合基因组、表观组、三维基因组等对1p13.2开展了多组学功能分析，发现多个CTTNBP2NL启动子区的骨密度因果性SNPs位于多种增强子表观修饰上，并通过染色质成环远距离调控WNT2B基因表达。我们猜想这些SNPs也可能介导“Epromoter”发挥远程调控功能。本课题将联合多种分子功能实验，系统验证“功能性SNP-Epromoter-WNT2B-骨代谢”的详细分子调控机制。研究结果有助于为基因启动子区非编码易感SNPs的遗传调控研究提供新思路。

Osteoporosis is a typical multiple-gene associated complex disease. Over 90% of osteoporosis risk SNPs are located in the noncoding regions of genome, leading to great challenge in deciphering the molecular regulatory mechanisms underlying them. 1p13.2 is a well-known osteoporosis susceptibility locus repeatedly reported by multiple independent studies. However, the precise molecular regulatory mechanisms at 1p13.2 are currently unknown. Recent report from Cell have found that susceptibility SNP within gene promoter could also act as enhancer to regulate distal target gene expression, and this kind of special dual promoter was called “Epromoter”. We have previously analyzed the functionality of 1p13.2 through integrating multi-omics resources including genome, epigenome and 3D genome, and found that several osteoporosis causal SNPs within CTTNBP2NL promoter region were annotated by multiple enhancer-related epigenetic makers and could regulate distal WNT2B gene expression through long-range looping formation. We therefore hypothesized that these SNPs might act as “Epromoter” to regulate distal gene. We will apply various experimental assays to systematically explore the precise molecular regulatory mechanisms underlying “functional SNP-Epromoter-WNT2B-osteoporosis” circuit at 1p13.2. Our research could provide new insights into deciphering molecular regulatory mechanisms underlying noncoding susceptibility SNPs within gene promoter region on complex diseases.