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Promoter sequence and architecture determine expression variability and confer robustness to genetic variants [GM12878]

ABSTRACT: Genetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability can be largely explained by a promoter’s DNA sequence and its binding sites for specific transcription factors. We show that promoter expression variability reflects the biological process of a gene, demonstrating a selective trade-off between stability for metabolic genes and plasticity for responsive genes and those involved in signaling. Promoters with a rigid transcription start site architecture are more prone to have variable expression and to be associated with genetic variants with large effect sizes, while a flexible usage of transcription start sites within a promoter attenuates expression variability and limits genotypic effects. Our work provides insights into the variable nature of responsive genes and reveals a novel mechanism for supplying transcriptional and mutational robustness to essential genes through multiple transcription start site regions within a promoter.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188099 | GEO | 2022/11/14

REPOSITORIES: GEO

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Project description:Despite overwhelming data that cigarette smoking causes chronic obstructive pulmonary disease (COPD), only a minority of chronic smokers are affected, strongly suggesting that genetic factors modify susceptibility to this disease. We hypothesized that there are individual variations in the response to cigarette smoking, with variability among smokers in expression levels of protective / susceptibility genes. Affymetrix arrays and TaqMan PCR were used to assess the variability of gene expression in the small airway epithelium obtained by fiberoptic bronchoscopy of 18 normal non-smokers, 18 normal smokers and 18 smokers with COPD. We identified 201 probesets representing 150 smoking-responsive genes that were significantly up- or down-regulated, and assessed the coefficient of variation in expression levels among the study population. Variation was a reproducible property of each gene as assessed by different microarray probesets and realtime PCR and was observed in both normal smokers and smokers with COPD. There was greater individual variability in smokers with COPD than in normal smokers. The majority of these highly variable smoking responsive genes were in the functional categories of signal transduction, xenobiotic degradation, metabolism, transport, oxidant-related and transcription. A similar pattern of the same highly variable genes was observed in an independent data set.We propose that there is likely genetic diversity within this subset of genes with highly variable individual to individual responses of the small airway epithelium to smoking, and this subset of genes represent putative candidates for assessment of susceptibility/protection from disease for future gene-based epidemiological studies for the risk of smokers for COPD. Experiment Overall Design: Affymetrix arrays and TaqMan PCR were used to assess the variability of gene expression in the small airway epithelium obtained by fiberoptic bronchoscopy of 18 normal non-smokers, 18 normal smokers and 18 smokers with COPD.

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Promoter sequence and architecture determine expression variability and confer robustness to genetic variants [GM12878]

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