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Genome-wide Analysis using ChIP to Identify Isoform-specific Gene Targets
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In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene

Ben Niu1, Denise M Coslo1, Alain R Bataille2

  • 1Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.

Nucleic Acids Research
|August 14, 2018
PubMed

Insights

Constitutive androstane receptor (CAR) plays a key role in liver biology. Species-specific CAR binding to DNA influences gene expression and liver tumor promotion, revealing critical differences between mice and humans.

Area of Science:

  • Molecular biology
  • Genomics
  • Toxicology

Background:

  • The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor involved in diverse biological processes.
  • Understanding species-specific differences in CAR function is crucial, particularly regarding its role in liver tumor promotion.

Purpose of the Study:

  • To investigate genome-wide binding of mouse and human CAR in the liver.
  • To identify species-specific CAR targets and their role in regulating biological pathways, including liver carcinogenesis.

Main Methods:

  • Development of transgenic mouse models expressing mouse and human CAR.
  • Genome-wide assessment of CAR binding using ChIP-exo assays upon activation with direct ligands and phenobarbital.
  • Integration of genomic data with transcriptional and pathway analyses.

Main Results:

  • Identification of novel CAR target genes, including Gdf15 and Foxo3, implicated in carcinogenesis.
  • Approximately 1000 genes showed differential binding between mouse and human CAR.
  • Mouse CAR preferentially bound to proto-oncogenes Myc and Ikbke, leading to mouse-specific transcriptional enhancement.
  • Distinct binding motifs were identified for mouse and human CAR.

Conclusions:

  • CAR is a key modulator of signaling pathways in mammals.
  • Species variation in CAR binding and transcriptional regulation contributes to differences in biological processes like liver cell proliferation and tumor promotion.
  • Provides a genomic context for understanding species-specific CAR effects.

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