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Alternative Promoter Use and Splice Variation in the Human Histamine H1 Receptor Gene

Division of Therapeutics and Molecular Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom

Correspondence and requests for reprints should be addressed to Caroline Swan, Division of Therapeutics and Molecular Medicine, D Floor, South Block, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom. E-mail: Caroline.Swan{at}nottingham.ac.uk

Upstream gene structure and mRNA expression of the human histamine H1 receptor gene was investigated in cells relevant to the pathogenesis of asthma, (primary cultured human airway smooth muscle (HASM) cells, primary cultured human bronchial epithelial cells and bronchial epithelial cell line [BEAS2B]), and other tissues known to express histamine H1 receptors (placenta and brain). Splice variation of the 5' terminal exons gave three separate locations for novel promoters upstream of the detected transcription start sites. Further splice variants in the 5' untranslated region were also observed. Transient transfections of promoter/luciferase constructs showed these regions directed expression in HASM cells and BEAS2B cells. Polymorphism screening of the major regulatory regions identified a number of novel single-nucleotide polymorphisms. Expression of splice variants was confirmed by real-time PCR assays. Results showed one 5' terminal exon splice variant, comprising exons B/K, expressed preferentially in all tissues. Interestingly, the other 5' terminal exon splice variants showed tissue-specific patterns of expression, with variant F/K expressed negligibly (0.1%) in HASM cells, but accounting for 19.3% and 8.3% of total expression in BEAS2B cells and differentiated human bronchial epithelial cells, respectively. Splice variant A/K was second most highly expressed in differentiated human bronchial epithelial cells (23%), whereas its expression in BEAS2B and HASM cells was 1.7% and 4.4%, respectively. These data suggest the use of alternative promoters directing human H1 receptor gene expression, both within and between cell types.

Key Words: asthma • histamine H1 receptor gene • messenger RNA • promoter • splice-variation

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