Epigenetic Regulation of Pregnane X Receptor Activity

Pregnane X receptor (PXR, NR1I2) is a ligand-dependent nuclear receptor (NR) that functions as a xenobiotic sensor and effector in coordinately regulating expression of genes of the xenobiotic detoxification network. PXR exerts its transcriptional regulatory functions by dimerization with retinoic X receptor RXR, and PXR-RXR complex binds to specific DNA sequences for regulating gene expression. PXR functions are regulated at the epigenetic level by chromatin modifications, DNA methylation and noncoding RNA. Chromatin modifications are carried out, in part, through interaction with coregulator complexes, including steroid coactivators (SRCs), corepressors (NcoR/SMRT), hepatocyte nuclear factor 4 alpha, proliferator activated receptor γ coactivator 1 alpha and protein arginine methyltransferase 1. PXR can be modified by acetylation, phosphorylation and sumoylation, and the promoter of PXR can be methylated at the "CpG" island. These factors collectively determine the ways in which PXR activity can be regulated, thereby affecting the magnitude and duration of the PXR-regulated drug metabolic responses. Most studies of PXR focus on its role as a transcription factor, which is responsible for the generation of messenger RNA. Recent emerging evidence suggests that PXR regulates gene expression at both transcriptional and translational levels. This review highlights recent research on the epigenetic mechanisms that are found to be important for the gene-regulatory activity of PXR and discusses their implications in xenobiotic metabolism and adverse drug responses.