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Transcriptomic profiling identifies novel mechanisms of transcriptional regulation of the cytochrome P450 (Cyp)3a11 gene.

ABSTRACT: Cytochrome P450 (CYP)3A is the most abundant CYP enzyme in the human liver, and a functional impairment of this enzyme leads to unanticipated adverse reactions and therapeutic failures; these reactions result in the early termination of drug development or the withdrawal of drugs from the market. The transcriptional regulation mechanism of the Cyp3a gene is not fully understood and requires a thorough investigation. We mapped the transcriptome of the Cyp3a gene in a mouse model. The Cyp3a gene was induced using the mPXR activator pregnenolone-16alpha-carbonitrile (PCN) and was subsequently downregulated using lipopolysaccharide (LPS). Our objective was to identify the transcription factors (TFs), epigenetic modulators and molecular pathways that are enriched or repressed by PCN and LPS based on a gene set enrichment analysis. Our analysis shows that 113 genes were significantly upregulated (by at least 1.5-fold) with PCN treatment, and that 834 genes were significantly downregulated (by at least 1.5-fold) with LPS treatment. Additionally, the targets of the 536 transcription factors were enriched by a combined treatment of PCN and LPS, and among these, 285 were found to have binding sites on Cyp3a11. Moreover, the repressed targets of the epigenetic markers HDAC1, HDAC3 and EZH2 were further suppressed by LPS treatment and were enhanced by PCN treatment. By identifying and contrasting the transcriptional regulators that are altered by PCN and LPS, our study provides novel insights into the transcriptional regulation of CYP3A in the liver.

SUBMITTER: Taneja G

PROVIDER: S-EPMC6491424 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Transcriptomic profiling identifies novel mechanisms of transcriptional regulation of the cytochrome P450 (Cyp)3a11 gene.

Taneja Guncha G Maity Suman S Jiang Weiwu W Moorthy Bhagavatula B Coarfa Cristian C Ghose Romi R

Scientific reports 20190430 1

Cytochrome P450 (CYP)3A is the most abundant CYP enzyme in the human liver, and a functional impairment of this enzyme leads to unanticipated adverse reactions and therapeutic failures; these reactions result in the early termination of drug development or the withdrawal of drugs from the market. The transcriptional regulation mechanism of the Cyp3a gene is not fully understood and requires a thorough investigation. We mapped the transcriptome of the Cyp3a gene in a mouse model. The Cyp3a gene w ...[more]

PMID: 31040347

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Project description:Cytochrome P450s (CYPs) display significant inter-individual variation in expression, much of which remains unexplained by known CYP single-nucleotide polymorphisms (SNPs). Testis-specific Y-encoded-like proteins (TSPYLs) are transcriptional regulators for several drug-metabolizing CYPs including CYP3A4 However, transcription factors (TFs) that might influence CYP expression through an effect on TSPYL expression are unknown. Therefore, we studied regulators of TSPYL expression in hepatic cell lines and their possible SNP-dependent variation. Specifically, we identified candidate TFs that might influence TSPYL expression using the ENCODE ChIPseq database. Subsequently, the expression of TSPYL1/2/4 as well as that of selected CYP targets for TSPYL regulation were assayed in hepatic cell lines before and after knockdown of TFs that might influence CYP expression through TSPYL-dependent mechanisms. Those results were confirmed by studies of TF binding to TSPYL1/2/4 gene promoter regions. In hepatic cell lines, knockdown of the REST and ZBTB7A TFs resulted in decreased TSPYL1 and TSPYL4 expression and increased CYP3A4 expression, changes reversed by TSPYL1/4 overexpression. Potential binding sites for REST and ZBTB7A on the promoters of TSPYL1 and TSPYL4 were confirmed by chromatin immunoprecipitation. Finally, common SNP variants in upstream binding sites on the TSPYL1/4 promoters were identified and luciferase reporter constructs confirmed SNP-dependent modulation of TSPYL1/4 gene transcription. In summary, we identified REST and ZBTB7A as regulators of the expression of TSPYL genes which themselves can contribute to regulation of CYP expression and-potentially-of drug metabolism. SNP-dependent modulation of TSPYL transcription may contribute to individual variation in both CYP expression and-downstream-drug response phenotypes. SIGNIFICANCE STATEMENT: Testis-specific Y-encoded-like proteins (TSPYLs) are transcriptional regulators of cytochrome P450 (CYP) gene expression. Here, we report that variation in TSPYL expression as a result of the effects of genetically regulated TSPYL transcription factors is an additional factor that could result in downstream variation in CYP expression and potentially, as a result, variation in drug biotransformation.

Dataset Information

Transcriptomic profiling identifies novel mechanisms of transcriptional regulation of the cytochrome P450 (Cyp)3a11 gene.

Publications

Transcriptomic profiling identifies novel mechanisms of transcriptional regulation of the cytochrome P450 (Cyp)3a11 gene.

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