Journal Article

Structure of silent transcription intervals and noise characteristics of mammalian genes

Molina, Nacho, Naef, Felix, Nicolas, Damien, Zoller, Benjamin

2015

Overview

Mammalian transcription occurs stochastically in short bursts interspersed by silent intervals showing a refractory period. However, the underlying processes and consequences on fluctuations in gene products are poorly understood. Here, we use single allele time‐lapse recordings in mouse cells to identify minimal models of promoter cycles, which inform on the number and durations of rate‐limiting steps responsible for refractory periods. The structure of promoter cycles is gene specific and independent of genomic location. Typically, five rate‐limiting steps underlie the silent periods of endogenous promoters, while minimal synthetic promoters exhibit only one. Strikingly, endogenous or synthetic promoters with TATA boxes show simplified two‐state promoter cycles. Since transcriptional bursting constrains intrinsic noise depending on the number of promoter steps, this explains why TATA box genes display increased intrinsic noise genome‐wide in mammals, as revealed by single‐cell RNA‐seq. These findings have implications for basic transcription biology and shed light on interpreting single‐cell RNA‐counting experiments. Synopsis Analysis of transcriptional bursting from time‐lapse imaging of single alleles in mammalian cells identifies the kinetic structure of promoter cycles underlying refractoriness, and explains noise in mRNA abundance. Quantitative modeling of single allele time‐lapse recordings in mouse cells identifies minimal models of promoter cycles, which inform on the rate‐limiting steps responsible for refractory periods. The structure of promoter cycles is gene specific and independent of genomic location. Typically, five rate‐limiting steps underlie the silent periods of endogenous promoters, while minimal synthetic promoters exhibit only one. Promoter architecture constrains intrinsic noise depending on the structure of the promoter cycles, notably, TATA box genes display increased intrinsic noise in mammals, as confirmed in single‐cell RNA‐seq. Graphical Abstract Analysis of transcriptional bursting from time‐lapse imaging of single alleles in mammalian cells identifies the kinetic structure of promoter cycles underlying refractoriness, and explains noise in mRNA abundance.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley & Sons, Ltd,Springer Nature
• Subject: Animals / Biochemistry, Molecular Biology / Cell culture / Constraining / Cycle protein / EMBO33 / EMBO44 / Gene expression / Genes / Genomes / Intervals / Life Sciences / Mammals / Markov Chains / Mice / Mouse Embryonic Stem Cells - physiology / NIH 3T3 Cells / noise in mRNA counts / Population / promoter cycle / Promoter Regions, Genetic / Promoters / Refractory period / Ribonucleic acid / RNA / single‐cell time‐lapse analysis / Stem cells / stochastic gene expression / TATA Box / Time-Lapse Imaging - methods / Transcription / Transcription, Genetic / transcriptional bursting / Variation