DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples
CYP3As are important drug-metabolizing enzymes in the liver. The causes for large inter-person variability in CYP3A expression/activity remain poorly understood. DNA methylation broadly regulates gene expression and the developmental transition from fetal CYP3A7 to adult CYP3A4, and CpG methylation...
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2024-11-01
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| author | Joseph M. Collins Danxin Wang |
| author_facet | Joseph M. Collins Danxin Wang |
| author_sort | Joseph M. Collins |
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| description | CYP3As are important drug-metabolizing enzymes in the liver. The causes for large inter-person variability in CYP3A expression/activity remain poorly understood. DNA methylation broadly regulates gene expression and the developmental transition from fetal CYP3A7 to adult CYP3A4, and CpG methylation upstream of the CYP3A4 promoter is associated with its expression. However, because non-promoter CYP3A regulatory regions remain largely uncharacterized, how DNA methylation influences CYP3A expression has yet to be fully explored. We recently identified a distal regulatory region (DRR) that controls the expression of CYP3A4, CYP3A5, and CYP3A7. Here, we investigated the relationship between CYP3A expression and the methylation status of 16 CpG sites within the DRR in 70 liver samples. We found significant associations between DRR methylation and the expression of CYP3A5 and CYP3A7 but not CYP3A4, indicating differential CYP3A regulation by the DRR. Also, we observed a dynamic reduction in DRR DNA methylation during the differentiation of induced pluripotent stem cells to hepatocytes, which correlated with increased CYP3A expression. We then evaluated the relative contribution of genetic variants, TFs, and DRR DNA methylation on CYP3A expression in liver samples. Our results reinforce the DRR as a CYP3A regulator and suggest that DNA methylation may impact CYP3A-mediated drug metabolism. |
| format | Article |
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| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-a0feb471687f49d68f8827995fdea54e2025-08-20T01:54:03ZengMDPI AGMolecules1420-30492024-11-012922540710.3390/molecules29225407DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver SamplesJoseph M. Collins0Danxin Wang1Department of Pharmacotherapy and Translational Research, College of Pharmacy, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Pharmacotherapy and Translational Research, College of Pharmacy, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL 32610, USACYP3As are important drug-metabolizing enzymes in the liver. The causes for large inter-person variability in CYP3A expression/activity remain poorly understood. DNA methylation broadly regulates gene expression and the developmental transition from fetal CYP3A7 to adult CYP3A4, and CpG methylation upstream of the CYP3A4 promoter is associated with its expression. However, because non-promoter CYP3A regulatory regions remain largely uncharacterized, how DNA methylation influences CYP3A expression has yet to be fully explored. We recently identified a distal regulatory region (DRR) that controls the expression of CYP3A4, CYP3A5, and CYP3A7. Here, we investigated the relationship between CYP3A expression and the methylation status of 16 CpG sites within the DRR in 70 liver samples. We found significant associations between DRR methylation and the expression of CYP3A5 and CYP3A7 but not CYP3A4, indicating differential CYP3A regulation by the DRR. Also, we observed a dynamic reduction in DRR DNA methylation during the differentiation of induced pluripotent stem cells to hepatocytes, which correlated with increased CYP3A expression. We then evaluated the relative contribution of genetic variants, TFs, and DRR DNA methylation on CYP3A expression in liver samples. Our results reinforce the DRR as a CYP3A regulator and suggest that DNA methylation may impact CYP3A-mediated drug metabolism.https://www.mdpi.com/1420-3049/29/22/5407cytochrome P450sCYP3A4CYP3A5CYP3A7DNA methylationgene expression |
| spellingShingle | Joseph M. Collins Danxin Wang DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples Molecules cytochrome P450s CYP3A4 CYP3A5 CYP3A7 DNA methylation gene expression |
| title | DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples |
| title_full | DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples |
| title_fullStr | DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples |
| title_full_unstemmed | DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples |
| title_short | DNA Methylation in the CYP3A Distal Regulatory Region (DRR) Is Associated with the Expression of CYP3A5 and CYP3A7 in Human Liver Samples |
| title_sort | dna methylation in the cyp3a distal regulatory region drr is associated with the expression of cyp3a5 and cyp3a7 in human liver samples |
| topic | cytochrome P450s CYP3A4 CYP3A5 CYP3A7 DNA methylation gene expression |
| url | https://www.mdpi.com/1420-3049/29/22/5407 |
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