ATP8B1 gene expression is driven by a housekeeping-like promoter independent of bile acids and farnesoid X receptor.
2012
Background Mutations in ATP8B1 gene were identified as a cause of low γ-glutamyltranspeptidase
cholestasiswith variable phenotype, ranging from
Progressive Familial Intrahepatic Cholestasisto Benign Recurrent Intrahepatic
Cholestasis. However, only the coding region of ATP8B1 has been described. The aim of this research was to explore the regulatory regions, promoter and 5′untranslated region, of the ATP8B1 gene. Methodology/Principal Findings 5′
Rapid Amplificationof
cDNA Endsusing human liver and intestinal tissue was performed to identify the presence of 5′ untranslated
exons. Expression levels of ATP8B1 transcripts were determined by quantitative reverse-transcription PCR and compared with the non-variable part of ATP8B1. Three putative promoters were examined in vitro using a reporter gene assay and the main promoter was stimulated with
chenodeoxycholic acid. Four novel untranslated
exonslocated up to 71 kb upstream of the previously published
exon1 and twelve different splicing variants were found both in the liver and the intestine. Multiple transcription start sites were identified within
exon−3 and the proximal promoter upstream of this transcription start site cluster was proven to be an essential regulatory element responsible for 70% of total ATP8B1 transcriptional activity. In vitro analysis demonstrated that the main promoter drives constitutive ATP8B1 gene expression independent of bile acids. Conclusions/Significance The structure of the ATP8B1 gene is complex and the previously published transcription start site is not significant. The basal expression of ATP8B1 is driven by a housekeeping-like promoter located 71 kb upstream of the first protein coding
exon.
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