肝细胞癌易感性呈现性别差异，作为雌激素受体途径关键因子，FOXA1与ERɑ结合并共同调控HCC抗性基因的表达。我们前期研究发现，FOXA1基因变异和HCC易感性关联，其中顺式变异−173VNTR增强转录因子EGR1对FOXA1的转录，并通过连锁不平衡导致编码区Thr83Ala的等位表达不平衡；而反式变异Thr83Ala则减弱了FOXA1与ERɑ的相互作用，降低了对若干HCC抗性靶基因的表达；并且抗性衍生型Thr83在中国人群受正选择。本项目拟在独立人群验证FOXA1与HCC的关联，基于CRISPR/Cas9技术建立Thr83Ala突变体的细胞系和小鼠模型，分析FOXA1反式作用变异的体外和体内表型，并以ChIP-Seq技术鉴定突变体相关的Foxa1/ERɑ的功能性差异靶基因及网络。本项目有望建立FOXA1和HCC关联的遗传模型并阐明其体内表型和功能的生物学机制，丰富HCC进化遗传学新观点。

FOXA1 is the core component in ERɑ pathway and they co-regulate a panel of target genes in a functional interaction mode and are implicated in sexual dimorphism in Hepatocellular carcinoma (HCC) susceptibility. We have previously found that regulatory and coding variants of FOXA1 gene are associated with HCC risk. The trans-acting −173VNTR enhances the transactivation of FOXA1 by EGR1, a HCC related transcription factor, correlates with allelic expression imbalance of the coding variant Thr83Ala, which is in strong linkage disequilibrium with −173VNTR. FOXA1 Thr83Ala variant impairs its interaction with ERα and attenuates the transactivation toward their HCC protective target genes. Furthermore, we observed that the HCC protective derived allele FOXA1 Thr83 has been under positive selection in Chinese population. This proposal is aimed to validate the genetic association between FOXA1 and HCC, investigate the in vitro and in vivo phenotype of FOXA1 Thr83Ala using CRISPR/Cas9 gene editing technique, analyze its functional effects on the cistromes and target genes of Foxa1 and ERɑin DEN induced HCC mice model using ChIP-Seq strategy, and to reveal the underlying specific functional target genes and network for FOXA1 Thr83Ala using integrate genomics and bioinformatics tools. This study will construct the genetic model for the association between FOXA1 and HCC, uncover the phenotypic relevance and biological mechanism, broaden our knowledge on molecular epidemiology and evolutionary genetic of HCC.