Promoter Haplotypes of the ABCB1 Gene Encoding the P-Glycoprotein Differentially Affect Its Promoter Activity by Altering Transcription Factor Binding

Jordan T. Speidel, Meixiang Xu, Sherif Abdel-Rahman

Research output: Contribution to journalArticle

Abstract

Promoter single nucleotide polymorphisms (SNPs) of the ABCB1 gene, encoding the placental efflux transporter P-glycoprotein, can alter its expression and affect fetal exposure to therapeutics and environmental xenobiotics. SNPs are not arrayed as independent variants but as combinations forming defined haplotypes. Recently, we defined the haplotypes encompassing ABCB1 promoter SNPs and found that ABCB1 haplotypes differentially affect its promoter activity. The mechanism(s) by which ABCB1 haplotypes alter its promoter activity are not known. We hypothesize that the haplotype-dependent differences in ABCB1 promoter activity are due to haplotype-specific alterations in transcription factor (TF) binding. To test our hypothesis, we used a TF binding profile array and determined whether differences in TF binding exist across different ABCB1 haplotypes. TFs showing significant haplotype binding differences were mechanistically evaluated using small interfering RNA (siRNA) in cultured human placental cells. Our data indicate significant haplotype-dependent differences in TF binding. Our siRNA studies showed that the regulatory effects of TFs on promoter activity are also haplotype dependent. Our data provide a mechanistic explanation for the differential effects of ABCB1 haplotypes on its promoter activity and underscore the importance of evaluating genetic variants in the context of haplotypes rather than individual SNPs when investigating their effects on gene/protein expression and disease risk.

Original languageEnglish (US)
Pages (from-to)973-981
Number of pages9
JournalDNA and Cell Biology
Volume37
Issue number12
DOIs
StatePublished - Dec 1 2018

Fingerprint

P-Glycoprotein
Haplotypes
Transcription Factors
Genes
Single Nucleotide Polymorphism
Small Interfering RNA
Xenobiotics
Gene Expression

Keywords

  • ABCB1 expression
  • haplotypes
  • P-glycoprotein
  • SNPs
  • transcription factors

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Promoter Haplotypes of the ABCB1 Gene Encoding the P-Glycoprotein Differentially Affect Its Promoter Activity by Altering Transcription Factor Binding. / Speidel, Jordan T.; Xu, Meixiang; Abdel-Rahman, Sherif.

In: DNA and Cell Biology, Vol. 37, No. 12, 01.12.2018, p. 973-981.

Research output: Contribution to journalArticle

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