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In Vivo Genome-Wide Binding Interactions of Mouse and Human Constitutive Androstane Receptors Reveal Novel Gene Targets Ben Niu1, Denise M

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In Vivo Genome-Wide Binding Interactions of Mouse and Human Constitutive Androstane Receptors Reveal Novel Gene Targets Ben Niu1, Denise M Published online 8 August 2018 Nucleic Acids Research, 2018, Vol. 46, No. 16 8385–8403 doi: 10.1093/nar/gky692 In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets Ben Niu1, Denise M. Coslo1, Alain R. Bataille2, Istvan Albert2, B. Franklin Pugh2 and Curtis J. Omiecinski1,* 1Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA and 2Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA Received May 04, 2018; Revised July 17, 2018; Editorial Decision July 19, 2018; Accepted July 20, 2018 ABSTRACT tion factors that are activated by direct ligands (1) and gen- erally share a common structure, an N-terminal A/B do- The constitutive androstane receptor (CAR; NR1I3) main, a DNA binding domain (DBD), a hinge domain, a is a nuclear receptor orchestrating complex roles ligand binding/ heterodimerization domain (LBD) and an in cell and systems biology. Species differences in F domain at the C-terminal (2). Upon ligand activation, CAR’s effector pathways remain poorly understood, the LBD would utilize activation function-2 (AF-2) to me- including its role in regulating liver tumor promotion. diate co-regulator interactions (3). However, CAR is dis- We developed transgenic mouse models to assess tinguished from other nuclear receptors in that it lacks an genome-wide binding of mouse and human CAR, A/B domain and is constitutively active in the absence of following receptor activation in liver with direct lig- ligand due to a charge-charge interaction between LBD he- ands and with phenobarbital, an indirect CAR acti- lixes that mimic an active AF-2 conformation, and therefore vator. Genomic interaction profiles were integrated capable of co-activator protein interactions in the absence of ligand (4). with transcriptional and biological pathway analyses. CAR was initially characterized as a xenobiotic Newly identified CAR target genes included Gdf15 metabolism modulator. Classified as a Class II nuclear re- and Foxo3, important regulators of the carcinogenic ceptor, another unusual property of CAR is its retention in process. Approximately 1000 genes exhibited dif- the cytosol in a phosphorylated state, but upon xenobiotic ferential binding interactions between mouse and sensing, it undergoes dephosphorylation, translocates into human CAR, including the proto-oncogenes, Myc the nucleus, and subsequently binds specific DNA motifs to and Ikbke, which demonstrated preferential bind- coordinately regulate transcription of target genes. Targets ing by mouse CAR as well as mouse CAR-selective include genes that encode drug metabolizing functions, transcriptional enhancement. The ChIP-exo analyses such as the Phase I cytochrome P450s, Phase II transferases also identified distinct binding motifs for the respec- and Phase III transporters (5–7). With respect to its role tive mouse and human receptors. Together, the re- in xenobiotic regulation, CAR contributes to regulating the metabolism of approximately 75% of clinically used sults provide new insights into the important roles drugs and is a major determinant in the detoxification of that CAR contributes as a key modulator of numer- environmental chemicals (6). Consequently, CAR is of ous signaling pathways in mammalian organisms, toxicological importance in safety evaluations for drug presenting a genomic context that specifies species discovery and in the development of industrial chemicals variation in biological processes under CAR’s con- destined for regulatory approval. trol, including liver cell proliferation and tumor pro- More recent evidence identified CAR’s broader roles motion. in regulating energy and lipid metabolism, cell prolifer- ation and carcinogenesis (6). For example, CAR is re- INTRODUCTION ported to suppress gluconeogenesis through its target- ing of genes such as phosphoenolpyruvate carboxykinase The constitutive androstane receptor (CAR) is a nuclear (PEPCK;PCK1) and glucose-6-phosphatase (G6PC), and receptor member (NR1I3) of the nuclear receptor super- functions to reverse induced-obesity in rodent models by family. Typically, nuclear receptors function as transcrip- *To whom correspondence should be addressed. Tel: +1 814 863 1625; Fax: +1 814 863 1696; Email: [email protected] C The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 8386 Nucleic Acids Research, 2018, Vol. 46, No. 16 regulating genes such as sterol regulatory element bind- (Clontech/Takara, Mountain View, CA, USA) to gener- ing protein 1 (SREBP1;SREBF1) (8). Studies of liver tu- ate yellow fluorescent protein N-terminal fusion CAR pro- morigenesis promoted by phenobarbital (PB) and 1,4-bis[2- tein constructs (YFP-hCAR and YFP-mCAR). All con- (3,5-dichloropyridyloxy)] benzene (TCPOBOP; TCP) re- structs were validated by DNA sequencing. Adenovirus vealed that CAR is essential for hepatic tumor progression (AV) constructs containing YFP-hCAR, YFP-mCAR and in initiation-promotion mouse models (9,10). Further stud- YFP-empty were produced in the Adeno X Expression Sys- ies have demonstrated that CAR induces growth arrest and tem (Clontech/Takara) and amplified to high titer by Sig- DNA-damage-inducible beta (GADD45B) and myelocyto- naGen (Rockville, MD, USA). blastosis oncogene (MYC), while altering microRNA ex- pression profiles related to hepatocarcinogenesis (11–13). Animals and treatments However, detailed roles for CAR’s participation in the car- cinogenic process are not well understood and are the sub- All animal care and experimental procedures complied with ject of some controversy in that chronic human exposures protocols approved by the Institutional Animal Care and to PB, a known CAR activator, have not been associated Use Committee of The Pennsylvania State University.Wild- with any detectable increase in human liver cancer incidence type (WT) C57BL/6 mice were purchased from Charles (14,15). Adding to its overall complexity, another unique River Laboratories (Wilmington, MA). Breeding pairs of feature of CAR among the nuclear receptors is that its ac- CAR -/- /pregnane X receptor (PXR) -/- double-knockout tivation pathways proceed through both direct ligand inter- (DBL KO) mice in the C57BL/6 background were a kind actions and through indirect signaling mechanisms (5,16). gift of Dr. Wen Xie (University of Pittsburg, Pittsburg, PA), The potential receptor conformational alterations inherent and their derivation was described previously (18). CAR in these respective activation pathways may result in differ- knockout (CAR -/-; CAR KO) mice were generated by ences in CAR genomic targeting, or in biological/ signal- crossing WT C57BL/6 mice with DBL KO mice. The mice ing outcomes, areas that have not been well characterized. were maintained under a standard 12 h light, 12 h dark cy- We hypothesized that differing DNA interaction profiles for cle at constant temperature (23 ± 1◦C) with 45–65% humid- the respective species CAR proteins, and perhaps variable ity. A total of six, 8-week-old male CAR -/- mice were in- chemical activation states, underlie the transcriptional pro- fected with YFP-hCAR AV (1 × 1012 virus particles/ml, grams driving differences in CAR’s biological function. ∼100 ul diluted injection volume per mouse) through tail- Due to technical limitations and poor availability of vein injection. At 72 and 94 h, the mice were administrated a chromatin immunoprecipitation (ChIP)-grade antibody, with two successive doses of PB (75mg/kg, in saline) (n = high-resolution genomic mapping for CAR has not been 3), or CITCO (5 mg/kg, in DMSO) (n = 3), through IP in- performed in vivo. In this investigation, we deployed ChIP- jection. Another six, 8-week-old male CAR -/- mice were exo, a modified ChIP-seq method incorporating exonucle- infected with YFP-mCAR AV constructs (1 × 1012 virus ase to trim crosslinking ChIP DNA (17), combined with particles/ml) through tail-vein injection. At 72 and 94 h, CAR-fusion proteins and a novel delivery system, to con- two successive doses of PB (75 mg/kg, in saline) (n = 3), duct high resolution, genome scale profiling for mouse and or TCPOBOP (2 mg/kg, in DMSO) (n = 3), were admin- human CAR (mCAR and hCAR) in vivo, using transgenic istrated. After 96 h, all AV-infected mice were harvested mouse models. With a view toward better definition of the for liver tissues after CO2 asphyxiation-induced euthanasia. role of CAR in carcinogenesis, we identified novel CAR ge- For non-adenovirus infected mice, 8-week-old male CAR - nomic interactions, referenced to published RNA-seq tran- /- mice (n = 6) and WT mice (n = 6) were administrated with scriptomic datasets. Further, we assessed CAR’s genomic a single dose of DMSO (4 ml/kg) (n = 3) or TCPOBOP interactions in the presence of direct vs. indirect activators, (2 mg/kg, in DMSO) (n = 3), through IP injection. After performed DNA motif analyses, assessed species differences 24 h, liver tissue extractions were performed following CO2 in CAR genomic binding profiles and identified specific
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