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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188131 | GEO | 2022/11/14

REPOSITORIES: GEO

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

Project description: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.

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Promoter sequence and architecture determine expression variability and confer robustness to genetic variants [immortalized lymphoblastoid cell lines]

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

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

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Promoter sequence and architecture determine expression variability and confer robustness to genetic variants [immortalized lymphoblastoid cell lines]

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Natural sequence variants of yeast environmental sensors confer cell-to-cell expression variability.

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Promoter architecture dictates cell-to-cell variability in gene expression.

Project description:Variability in gene expression among genetically identical cells has emerged as a central preoccupation in the study of gene regulation; however, a divide exists between the predictions of molecular models of prokaryotic transcriptional regulation and genome-wide experimental studies suggesting that this variability is indifferent to the underlying regulatory architecture. We constructed a set of promoters in Escherichia coli in which promoter strength, transcription factor binding strength, and transcription factor copy numbers are systematically varied, and used messenger RNA (mRNA) fluorescence in situ hybridization to observe how these changes affected variability in gene expression. Our parameter-free models predicted the observed variability; hence, the molecular details of transcription dictate variability in mRNA expression, and transcriptional noise is specifically tunable and thus represents an evolutionarily accessible phenotypic parameter.

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