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Reverse transcriptional profiling: non-correspondence of transcript level variation and proximal promoter polymorphism.

ABSTRACT: BACKGROUND: Variation in gene expression between two Drosophila melanogaster strains, as revealed by transcriptional profiling, seldom corresponded to variation in proximal promoter sequence for 34 genes analyzed. Two sets of protein-coding genes were selected from pre-existing microarray data: (1) those whose expression varied significantly and reproducibly between strains, and (2) those whose transcript levels did not vary. Only genes whose regulation of expression was uncharacterized were chosen. At least one kB of the proximal promoters of 15-19 genes in each set was sequenced and compared between strains (Oregon R and Russian 2b). RESULTS: Of the many promoter polymorphisms, 89.6% were SNPs and 10.4% were indels, including homopolymer tracts, microsatellite repeats, and putative transposable element footprints. More than half of the SNPs were changes within a nucleotide class. Hypothetically, genes differing in expression between the two strains should have more proximal promoter polymorphisms than those whose expression is similar. The number, frequency, and type of polymorphism, however, were the same in both sets of genes. In fact, the promoters of six genes with significantly different mRNA expression were identical in sequence. CONCLUSION: For these genes, sequences external to the proximal promoter, such as enhancers or in trans, must play a greater role than the proximal promoter in transcriptomic variation between D. melanogaster strains.

SUBMITTER: Brown RP

PROVIDER: S-EPMC1192798 | biostudies-literature | 2005

REPOSITORIES: biostudies-literature

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Reverse transcriptional profiling: non-correspondence of transcript level variation and proximal promoter polymorphism.

Brown Rebecca Petersen RP Feder Martin E ME

BMC genomics 20050817

<h4>Background</h4>Variation in gene expression between two Drosophila melanogaster strains, as revealed by transcriptional profiling, seldom corresponded to variation in proximal promoter sequence for 34 genes analyzed. Two sets of protein-coding genes were selected from pre-existing microarray data: (1) those whose expression varied significantly and reproducibly between strains, and (2) those whose transcript levels did not vary. Only genes whose regulation of expression was uncharacterized w ...[more]

PMID: 16107220

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Project description:BackgroundTyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Common genetic variation at the human TH promoter predicts alterations in autonomic activity and blood pressure, but how such variation influences human traits and, specifically, whether such variation affects transcription are not yet known.Methods and resultsPairwise linkage disequilibrium across the TH locus indicated that common promoter variants (C-824T, G-801C, A-581G, and G-494A) were located in a single 5' linkage disequilibrium block in white, black, Hispanic, and Asian populations. Polymorphisms C-824T and A-581G were located in highly conserved regions and were predicted to disrupt known transcriptional control motifs myocyte enhancer factor-2 (MEF2), sex-determining region Y (SRY), and forkhead box D1 (FOXD1) at C-824T and G/C-rich binding factors specificity protein 1 (SP1), activating enhancer-binding protein 2 (AP2)], early growth response protein 1 (EGR1) at A-581G. At C-824T and A-581G, promoter and luciferase reporter plasmids indicated differential allele strength (T>C at C-824T; G>A at A-581G) under both basal circumstances and secretory stimulation. C-824T and A-581G displayed the most pronounced effects on both transcription in cella and catecholamine secretion in vivo. We further probed the functional significance of C-824T and A-581G by cotransfection of trans-activating factors in cella; MEF2, SRY, and FOXD1 differentially activated C-824T, whereas the G/C-rich binding factors SP1, AP2, and EGR1 differentially activated A-581G. At C-824T, factor MEF2 acted in a directionally coordinate fashion (at T>C) to explain the in vivo trait associations, whereas at A-581G, factors SP1, AP2, and EGR1 displayed similar differential actions (at G>A). Finally, chromatin immunoprecipitation demonstrated that the endogenous factors bound to the motifs in cella.ConclusionsWe conclude that common genetic variants in the proximal TH promoter, especially at C-824T and A-581G, are functional in cella and alter transcription so as to explain promoter marker-on-trait associations in vivo. MEF2, FOXD1, and SRY contribute to functional differences in C-824T expression, whereas SP1, AP2, and EGR1 mediate those of A-581G. The SRY effect on TH transcription suggests a mechanism whereby male and female sex may differ in sympathetic activity and hence blood pressure. These results point to new strategies for diagnostic and therapeutic intervention into disorders of human autonomic function and their cardiovascular consequences.

Dataset Information

Reverse transcriptional profiling: non-correspondence of transcript level variation and proximal promoter polymorphism.

Publications

Reverse transcriptional profiling: non-correspondence of transcript level variation and proximal promoter polymorphism.

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