SNPs Outside Response Elements Impact Aryl Hydrocarbon Receptor (AHR) Binding and Gene Regulation: Genome‐wide SNP‐dependent Transcriptional Regulation

Abstract

BACKGROUNDMost functionally‐significant single nucleotide polymorphisms (SNPs) are outside of open reading frames. Mechanisms by which these SNPs contribute to gene regulation are poorly understood. Aryl hydrocarbon receptor (AHR) is a nuclear receptor that regulates drug metabolism, xenobiotic response and immune response. Our previous data indicate that SNPs outside response elements can impact transcription factor binding and gene regulation. We hypothesized that SNPs near but outside AHR response elements (AhREs) might impact AHR binding and gene regulation.METHODSWe have collected dense SNP‐genotypes across 300 lymphoblastoid cell lines (LCLs) – a powerful tool for generating and testing pharmacogenomic hypotheses. Eight LCLs were used to generate hypotheses about AHR SNP‐dependent transcription utilizing RNA‐ and ChIP‐seq, which were tested in additional LCLs using qRT‐PCR and ChIP after AHR agonist or antagonist treatment.RESULTS69 genes were highly significantly differentially expressed after agonist or antagonist treatment and 80% of those genes had an AhRE within 50kb. Five SNP‐gene pairs have been functionally validated in additional LCLs (Table 1).CONCLUSIONSNPs that are outside of AhREs can alter AHR binding and gene transcription. This is a general phenomenon that may have large‐scale influence on gene transcriptional regulation and pharmacogenomics.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.