增强子对于调节组织特异性基因表达至关重要，增强子区域内的遗传变异被认为有助于各种癌症相关过程，包括治疗耐药性。然而，确切的机制仍然难以捉摸。利用明确的药物基因对，我们鉴定了二氢嘧啶脱氢酶（DPD、DPYD 基因）表达的增强子区域，该区域与抗癌药物 5-氟尿嘧啶（5-FU）的代谢相关。使用报告系统、CRISPR基因组编辑的细胞模型和人类肝脏标本，我们在体外和体内证明了位于这种新型增强子内的常见种系变异（rs4294451；27%的总体次要等位基因频率）的基因型状态控制DPYD转录并改变抗性至5-FU。变异基因型增加了转录因子CEBPB向增强子的募集，并改变了增强子和DPYD启动子之间直接相互作用的水平。我们的数据提供了对控制 5-FU 敏感性和耐药性的监管机制的深入了解。

Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.