Activators of CAR and PXR Rapidly Alter Chromatin Accessibility in Mouse Liver

Abstract

CAR and PXR are important xenobiotic sensors that rapidly induce and repress genes regulating diverse liver metabolic processes, including drug, steroid and lipid metabolism. The effects of specific activators of CAR and PXR on mouse liver chromatin accessibility were determined using DNase‐Seq to identify global changes in DNase hypersensitive sites (DHS) 3 hr after treatment of mice with TCPOBOP (CAR activation) or PCN (PXR activation). Differential DHS analysis (ΔDHS) identified 928 TCPOBOP‐induced DHS and 161 TCPOBOP‐repressed DHS, as well as 1,062 PCN‐induced DHS and 390 PCN‐repressed DHS, with some overlap between the two sets of ΔDHS. Thus, CAR and PXR rapidly induce large numbers of localized changes in chromatin accessibility. Several ΔDHS were confirmed by qPCR, including ΔDHS upstream of the CAR target gene Cyp2b10. The ΔDHS were not randomly distributed: mapping ΔDHS to their presumed targets (i.e., the nearest gene within 100 kb) revealed strong (11.4‐fold) enrichment (p<E‐19) of the TCPOBOP‐induced DHS in the set of TCPOBOP‐induced genes, identified in the same livers. The gene targets of TCPOBOP‐induced DHS also showed strong enrichment (5.9‐fold, p<0.005) in the set of TCPOBOP‐repressed genes. Thus, chromatin opening is associated with rapid activation as well as rapid repression of CAR target genes. We also found strong enrichment (11.7‐fold, p<E‐29) of target genes of PCN‐induced DHS in the PCN‐inducible gene set, whereas genes repressed by PCN were significantly enriched (6.4‐fold, p<E‐04) in PCN‐repressible DHS gene targets. Thus, CAR and PXR may repress genes by fundamentally different mechanisms: DHS opening for CAR vs. DHS closing for PXR.