In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets

Ben Niu, Denise M. Coslo, Alain R. Bataille, Istvan Albert, B. Franklin Pugh, Curtis J. Omiecinski

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.

Original languageEnglish (US)
Pages (from-to)8385-8403
Number of pages19
JournalNucleic acids research
Volume46
Issue number16
DOIs
StatePublished - Jan 1 2018

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Genome
Genes
Liver
Biological Phenomena
Systems Biology
Proto-Oncogenes
Phenobarbital
Cytoplasmic and Nuclear Receptors
Transgenic Mice
Cell Biology
Neoplasms
Cell Proliferation
constitutive androstane receptor
Ligands

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Niu, Ben ; Coslo, Denise M. ; Bataille, Alain R. ; Albert, Istvan ; Franklin Pugh, B. ; Omiecinski, Curtis J. / In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets. In: Nucleic acids research. 2018 ; Vol. 46, No. 16. pp. 8385-8403.
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In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets. / Niu, Ben; Coslo, Denise M.; Bataille, Alain R.; Albert, Istvan; Franklin Pugh, B.; Omiecinski, Curtis J.

In: Nucleic acids research, Vol. 46, No. 16, 01.01.2018, p. 8385-8403.

Research output: Contribution to journalArticle

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