Transcriptional and Post-transcriptional Regulation of ATP-binding Cassette Transporter Expression

ATP binding cassette (ABC) transporters are a family of proteins whose activity is vital to cell detoxification, protection against xenobiotics and oxidative stress, and maintenance of homeostasis of endogenous compounds. Subtle changes in endogenous expression level of these transporters can have significant clinical implications. In particular, the impact of such variation on the role of ABC transporters in transport of pharmaceutical agents is of interest; inter-individual differences in expression of ABC transporters can result in changes in exposure to pharmaceutical agents or their metabolites, leading to altered drug efficacy or drug-induced toxicities. Variation in gene expression can be caused by a number of factors that modulate the "normal" activity during transcription or translation. In this study, mechanisms that regulate mRNA or protein expression of ATP-binding cassette transporters were characterized in human tissues. First, the impact of DNA sequence variation on mRNA expression across individuals was evaluated in the human kidney. Several expression quantitative trait loci (eQTLs) were identified for ABC transporters in the kidney, and one eQTL for ABCG2 (BCRP) was validated in an in vitro reporter-gene assay. Next, the role of alternative splicing in regulation of transporter expression was explored using transcriptome sequencing data from multiple individuals in several human tissues. Examples of splicing events that were found to modulate transporter expression across individuals include alternate 5 prime untranslated regions (5' UTRs) in the genes ABCC5 and ABCA8. Further, a splicing event in the gene ABCC6 was identified that produces a premature termination codon, triggering the nonsense mediated decay process; this event may be responsible for regulating inter-tissue expression of ABCC6. Finally, transcription factor regulators of ABC transporters were identified by searching for transcription factor binding motif enrichment in sets of genes co-expressed with ABC transporters in several human tissues. A number of potential transcriptional regulators of transporters were identified