In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets
Open accessAbstract
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.
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The effects of the CAR-driven c-Myc-Foxm1 axis are not recapitulated in humanized CAR transgenic mice or human hepatocytes.
“these effects are not recapitulated in humanized CAR transgenic mice or human hepatocytes,45, 46, 47”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [45]
The Discussion (page unavailable) reports much weaker Myc induction in humanized CAR mice than in wild-type mice, supporting a species difference, but not a complete absence of the effect. The Results (page unavailable) do not establish that a c-Myc–Foxm1 axis fails to occur in human hepatocytes; the paper discusses FOXO3, not Foxm1, in relation to Myc. (LLM, conf=0.86)
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Xenobiotic Receptor CAR Is Highly Induced in Psoriasis and Promotes Keratinocyte Proliferation
Lai, B., Xie, X., Li, F., Cui, Q., Dang, E., Luo, W., Wang, N., Zheng, Y., Wang, G., Xiao, L., et al. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.05.017 · Cited by 5 · see citing works
HDI-STARR-seq: Condition-specific enhancer discovery in mouse liver in vivo
Chang, T.-Y., & Waxman, D. J. (2024) · BMC Genomics · doi:10.1186/s12864-024-11162-9 · Cited by 4 · see citing works
Bile acid regulation of xenobiotic nuclear receptors on the expressions of orosomucoids in the liver
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HNF4α contributes to hepatic CAR dysfunction in polymicrobial sepsis
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CAR/Nr1i3 directs T cell adaptation to bile acids in the small intestinePreprint
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- Authors
- Niu, B., Coslo, D. M., Bataille, A. R., Albert, I., Pugh, B. F., & Omiecinski, C. J.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- Omiecinski, Curtis J
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-08-08
- Volume
- 46
- Issue
- 16
- Pages
- 8385-8403
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC6144799
- OpenAlex
- W2890819992
- Cited by
- 37
- References
- 74
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 2 · 2018: 3
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM066411)
- National Environmental Health Sciences Institute (ES013768)
- U.S. Department of Agriculture (2014-06624)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- constitutive androstane receptor, nuclear receptor binding sites, species differences, human-mouse comparison, liver tumor promotion, GDF15, FOXO3, c-Myc, IKBKE, transcriptional regulation, binding motifs, liver cell proliferation, ChIP-exo
- MeSH terms
- Forkhead Box Protein O3, Constitutive Androstane Receptor, Androstanes, Animals, DNA-Binding Proteins, Humans, Ligands, Liver, Liver Neoplasms, Mice, Transgenic, Protein Binding, Genes, myc, Genome, Receptors, Cytoplasmic and Nuclear, Hepatocytes, Cell Proliferation, Mice, I-kappa B Kinase, Growth Differentiation Factor 15
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