Alternative splicing and tissue-specific transcription of human and rodentubiquitous 5-aminolevulinate synthase (ALAS1) genes

The rate of haem synthesis in non-erythroid mammalian tissues is controlled by the ubiquitous isoform of 5-aminolevulinate synthase (ALASI). In order to explore the regulation of mammalian ALASI genes, we have investigated th e transcription of the human and rat genes. The 17 kb human gene differs fr om the rat gene in containing an additional untranslated exon that is alter natively spliced to produce a longer, minor mRNA transcript. Relative amoun ts of the two transcripts were similar in all tissues examined. Analysis of mRNA transcripts in human and rat tissues revealed tissue-specific differe nces in the use of transcription start sites by closely similar core promot ers. In brain, initiation was from sites within and upstream from the TATA box, including an initiator-like element. In liver, initiation was TATA-dri ven from a single downstream site that appeared to be used exclusively for induction by drugs. Intermediate patterns were observed in other tissues an d cell lines. Mutation of the TATA box did not impair transcription in tran sfected HeLa cells but activated upstream start sites, recapitulating the b rain pattern. Our findings indicate that the conformation of the core ALAS1 promoter that directs assembly of the transcription pre-initiation complex may vary between tissues and have implications for understanding the tissu e-specific regulated expression of this gene. (C) 2001 Elsevier Science B.V . All rights reserved.