Gotoh-Saito Saki, Wada Ryoko, Nishimura Tomoe, Kawaji Hideya
Research Center for Genome & Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Nat Commun. 2025 Apr 29;16(1):3851. doi: 10.1038/s41467-025-59132-3.
Genomic variation drives phenotypic diversity, including individual differences in drug response. While coding polymorphisms linked to drug efficacy and adverse reactions are well characterized, the contribution of noncoding regulatory elements remains underexplored. Using CAGE (Cap Analysis of Gene Expression), profiling transcription initiations of mRNAs and enhancer RNAs, we identify candidate cis-regulatory elements (CREs) and assessed their activities simultaneously in HepG2 cells expressing the drug-responsive transcription factor pregnane X receptor (PXR). Comparison with GWAS data reveals strong enrichment of the drug-induced CREs near variants associated with bilirubin and vitamin D levels. Among those bound by PXR in primary hepatocytes, we identify enhancers of UGT1A1, TSKU, and CYP24A1 and functional alleles that alter regulatory activities. We also find that TSKU influences expression of vitamin D-metabolizing enzymes. This study expands the landscape of PXR-mediated regulatory elements and uncovers noncoding variants impacting drug response, providing insights into the genomic basis of adverse drug reactions.
基因组变异驱动表型多样性，包括药物反应的个体差异。虽然与药物疗效和不良反应相关的编码多态性已得到充分表征，但非编码调控元件的作用仍未得到充分探索。我们使用CAGE（基因表达的帽分析）对mRNA和增强子RNA的转录起始进行分析，在表达药物反应性转录因子孕烷X受体（PXR）的HepG2细胞中鉴定候选顺式调控元件（CRE）并同时评估其活性。与全基因组关联研究（GWAS）数据的比较揭示了药物诱导的CRE在与胆红素和维生素D水平相关的变异附近的强烈富集。在原代肝细胞中被PXR结合的元件中，我们鉴定出UGT1A1、TSKU和CYP24A1的增强子以及改变调控活性的功能等位基因。我们还发现TSKU影响维生素D代谢酶的表达。这项研究扩展了PXR介导的调控元件的范围，揭示了影响药物反应的非编码变异，为药物不良反应的基因组基础提供了见解。
