
DPYD 유전자 발현은 rs4294451 유전형에 따라 달라지며, 이는 CEBPB 전사인자의 결합 능력 차이에 의해 조절된다.


coremsg

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.

### Competing Interest Statement

SMO reports former research support from Processa Pharmaceuticals, Inc., which are outside of the conduct of this study. SMO is an independent consultant for Processa Pharmaceuticals, Inc., in matters not related to this study. FI is currently an AbbVie employee and receives stocks from the company.

Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD)

항암-약물-대사-유전자-dihydropyrimidine-dehydrogenase-dpyd-의-후생유전학적-조절을-결정하는-생식세포-cis-변이


항암 약물 대사 유전자 dihydropyrimidine dehydrogenase(DPYD)의 후생유전학적 조절을 결정하는 생식세포 cis 변이
