Highly Variable Expression of ESR1 Splice Variants in Human Liver: Implication in the Liver Gene Expression Regulation and Inter-Person Variability in Drug Metabolism and Liver Related Diseases

Estrogen receptor alpha (ESR1) plays an important role in many tissues including the liver. Numerous alternative splice variants of ESR1 exist that encode ESR1 proteins with varying functions. We aim to study ESR1 genomic organization and its mRNA expression profile in human liver by incorporating information from literature and genomic databases (Ensembl, NCBI and GTEx), and employing a quantitative method to measure all known ESR1 mRNA splice variants in 36 human livers. We re-constructed ESR1 genomic organization map that contains 29 exons. ESR1 mRNA splice variants with varying 5’ untranslated region (5’UTR) and/or missing each of eight coding exons are readily detectable in liver and other tissues. Moreover, we found extensive inter-individual variability in splice variant pattern of ESR1 transcripts. Specifically, ESR1 transcripts lacking first coding exon are the main transcripts in liver, which encode ESR1 proteins missing N-terminal 173 amino acids (for example, ERα46), reported previously to have either constitutive activity or dominant negative effects depending on cellular context. Moreover, some livers predominantly express ESR1 transcripts missing exon 10 or 16, encoding C-terminal truncated ESR1 proteins with varying ESR1 activities. Inter-person variability in ESR1 expression profile may contribute to inter-person variability in drug metabolism and susceptibility to liver related diseases.