Data from: Widespread epigenetic changes to the enhancer landscape of mouse liver induced by a specific xenobiotic agonist ligand of the nuclear receptor CAR

CAR (Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug,
steroid and lipid metabolism and dysregulates genes linked to
hepatocellular carcinogenesis, but its impact on the liver epigenome is
poorly understood. TCPOBOP, a halogenated xenochemical and highly specific
CAR agonist ligand, induces localized chromatin opening or closing at
several thousand mouse liver genomic regions, discovered as differential
DNase-hypersensitive sites (ΔDHS). Active enhancer and promoter histone
marks induced by TCPOBOP were enriched at opening DHS and
TCPOBOP-inducible genes. Enrichment of CAR binding and CAR motifs was seen
at opening DHS and their inducible drug/lipid metabolism gene targets, and
at many constitutively open DHS located nearby. TCPOBOP-responsive cell
cycle and DNA replication genes co-dependent on MET/EGFR signaling for
induction were also enriched for CAR binding. A subset of opening DHS and
many closing DHS mapping to TCPOBOP-responsive target genes did not bind
CAR, indicating an indirect mechanism for their changes in chromatin
accessibility. TCPOBOP-responsive DHS were also enriched for induced
binding of RXRA, CEBPA and CEBPB, and for motifs for liver-enriched
factors that may contribute to liver-specific transcriptional responses to
TCPOBOP exposure. These studies elucidate the enhancer landscape of
TCPOBOP-exposed liver and the widespread epigenetic changes that are
induced by both direct and indirect mechanisms linked to CAR activation.
The global maps of thousands of environmental chemical-induced epigenetic
changes described here constitute a rich resource for further research on
xenochemical effects on liver chromatin states and the epigenome.