Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression
Copyright policy )Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression
We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 5' segment, spanning common DNA sequence variations, T-261G, A-161T, and -182INS/DEL-181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype -261G_-182INS-181_A-161 enhanced transcriptional activity 2.3-fold compared with the haplotype T-261_-182INS-181_A-161. Conversely, -161T reversed this, and the net effect when -261G and -161T were in the same haplotype (-261G_-182INS-181_-161T) was equivalent to the major haplotype (T-261_-182INS-181_A-161). Electrophoretic mobility shift experiments showed that -261G and -161T modify the binding of transcription factors (TFs): -261G generates a new AP2 binding site, while alleles A-161 and -161T exhibit different binding characteristics to AP1. T-261G and A-161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies.
- University of Chicago United States
- University of Queensland Australia
- Icahn School of Medicine at Mount Sinai United States
- University of Pennsylvania United States
- Park Centre for Mental Health Australia
Transcriptional Activation, Biochemistry & Molecular Biology, 570, Oligonucleotides, Snp, Gene Expression, CHO Cells, Single-nucleotide Polymorphisms, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Association, 5-ht1b Receptor, C1, Gene Frequency, Cricetinae, Animals, Humans, Promoter Regions, Genetic, Fluorescence-polarization, 321021 Psychiatry, Psychiatry, C-jun, Mental Disorders, Neurosciences, Promoter, 730211 Mental health, Binding, Transcription Factor AP-1, Haplotypes, Htr1b, Receptor, Serotonin, 5-HT1B, Schizophrenia, 5' Untranslated Regions, Transcription, Alcohol Dependence
Transcriptional Activation, Biochemistry & Molecular Biology, 570, Oligonucleotides, Snp, Gene Expression, CHO Cells, Single-nucleotide Polymorphisms, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Association, 5-ht1b Receptor, C1, Gene Frequency, Cricetinae, Animals, Humans, Promoter Regions, Genetic, Fluorescence-polarization, 321021 Psychiatry, Psychiatry, C-jun, Mental Disorders, Neurosciences, Promoter, 730211 Mental health, Binding, Transcription Factor AP-1, Haplotypes, Htr1b, Receptor, Serotonin, 5-HT1B, Schizophrenia, 5' Untranslated Regions, Transcription, Alcohol Dependence
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