title: Structure of silent transcription intervals and noise characteristics of mammalian genes.
abstract: 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.
authors.affiliation: The Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zoller
authors.affiliation: The Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Damien
authors.initials: D
authors.lastname: Nicolas
authors.affiliation: The Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Nacho
authors.initials: N
authors.lastname: Molina
authors.affiliation: The Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland felix.naef@epfl.ch.
authors.forename: Felix
authors.initials: F
authors.lastname: Naef
mesh_terms: D000818:Animals; D008390:Markov Chains; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D016385:TATA Box; D059008:Time-Lapse Imaging / Q000379:methods*; D014158:Transcription, Genetic
keywords: noise in mRNA counts; promoter cycle; single‐cell time‐lapse analysis; stochastic gene expression; transcriptional bursting