Genetic polymorphisms in the RNA polymerase II core promoter and enhancer elements of the UGT1A1 promoter influence activation of its gene transcription

Abstract

RNA polymerase II core promoter and enhancer/repressor elements are involved in regulation of gene transcription. The objective of this study is to examine whether genetic polymorphisms in these elements can change regulation of gene transcription. Genetic polymorphisms in the UGT1A1 promoter were evaluated, which include polymorphism of (TA)6/7TAA (*1/*28) in the TATA box, and two SNPs (−3279 T>G *60 and .C3156 G>A*93) in the distal enhancer elements. These polymorphisms in 100 human liver samples were genotyped by sequencing or microarray chips. mRNA levels of UGT1A1 and 9 transcriptional factors (PXR, CAR, PPARa, GR, Nrf2, AhR, HNF1a, HFN4a, and CEBPa) were quantified by the bDNA technique. Associations were established by multiple linear regressions with adjustment for confounders. Correlations of gene transcription between UGT1A1 and each of the 9 transcriptional factors were observed in the samples carrying genotypes of *1/*1 and *1/*28. However, such correlations did not exist in the samples carrying combinational genotypes of *28/*28 with *60/*60 or *93/*93, which also associated with significantly lower UGT1A1 mRNA levels. Polymorphisms in both RNA polymerase II core promoter and enhancer elements of the UGT1A1 promoter may have a synergetic effect on regulation of UGT1A1 transcription, but the mechanisms need to be investigated. This work was supported by NIH COBRE 5P20 RR021940.