A paper on a comprehensive analysis of drug-induced enhancers involved in drug side effects has been published

A research group of Dr. Hideya Kawaji, Center Director of the Tokyo Metropolitan Institute of Medical Science (TMiMS), and his colleagues published a research article in "Nature Communications" on Apr 29, 2025, which comprehensively analyzed drug-induced enhancers involved in adverse drug reactions. TMiMS issued a press release on the same day.

Drug efficacy and adverse reactions vary among individuals, and genetic factors are known to contribute to these differences. Many studies have focused on the relationship between genetic polymorphisms in protein coding regions and individual responses to drugs. Meanwhile, a part of genomic regions that do not code proteins (non-coding regions) also play a role to regulate gene expression as cis-regulatory elements, such as promoters and enhancers. It has recently been shown that trait-associated single nucleotide polymorphisms are enriched in these regions. Dr. Hideya Kawaji and his colleagues have been studying the identification of cis-regulatory elements based on genome-wide profiles of transcription initiation sites of messenger RNA and RNA derived from enhancer regions (enhancer RNA, eRNA) in single nucleotide resolution.

In this study, they discovered novel enhancers bound by the drug-activated nuclear receptor PXR (pregnane X receptor) in hepatocytes and showed that these enhancers upregulate the gene expression of drug-responsive genes. It revealed a new molecular mechanism that the drug administration activates the enhancers, and they subsequently activates the expression of a drug-metabolizing enzyme UGT1A1, a vitamin D-inactivating enzyme CYP24A1, and TSKU which affects the expression of genes related to vitamin D metabolism. Vitamin D deficiency has been reported as an adverse reaction of several drugs, and this is the first finding to indicate molecular mechanism underlying the reaction, according to the press release.

All these cis-regulatory elements reported in this paper were identified from the CAGE (Cap Analysis of Gene Expression) data obtained from a model system of human hepatocyte and the "CREate method", an algorithm to identify the cis-regulatory elements with high sensitivity. A database "fanta.bio ", which is being developed by Director Hideya Kawaji as Co-Principal Investigator, contains cis-regulatory elements in various cells identified through application of the CREate method to publicly available CAGE data. This study revealed a new molecular mechanism of drug response, underlined the importance of cis-regulatory elements in non-coding regions, and demonstrated the relevance of the cis-regulatory regions provided in fanta.bio. The database fanta.bio is expected to contribute to studies elucidating cis-regulatory elements and their impacts on diseases, etc, as a foundation in functional genomics.

For more details, please see the published article "Drug-induced cis-regulatory elements in human hepatocytes affect molecular phenotypes associated with adverse reactions" and the press release "Discovery of a new genomic regulatory region involved in the mechanism of drug side effects - Comprehensive analysis of drug-induced enhancers in human hepatocytes -" .

fanta.bio is developed as a part of JST Database Integration Coordination Program (DICP), "Construction of an integrative data platform for transcriptional regulations".