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Contributions of regulated transcription and mRNA decay to the dynamics of gene expression

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Organisms have acquired sophisticated regulatory networks that control gene expression in response to cellular perturbations. Understanding of the mechanisms underlying the coordinated changes in gene expression in response to external and internal stimuli is a fundamental issue in biology. Recent advances in high‐throughput technologies have enabled the measurement of diverse biological information, including gene expression levels, kinetics of gene expression, and interactions among gene expression regulatory molecules. By coupling these technologies with quantitative modeling, we can now uncover the biological roles and mechanisms of gene regulation at the system level. This review consists of two parts. First, we focus on the methods using uridine analogs that measure synthesis and decay rates of RNAs, which demonstrate how cells dynamically change the regulation of gene expression in response to both internal and external cues. Second, we discuss the underlying mechanisms of these changes in kinetics, including the functions of transcription factors and RNA‐binding proteins. Overall, this review will help to clarify a system‐level view of gene expression programs in cells. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Turnover and Surveillance > Regulation of RNA Stability RNA Methods > RNA Analyses in vitro and In Silico
Scheme of genome‐wide measurements for RNA kinetics using pulse labeling with uridine analogs. (a) BRIC‐seq: BrU‐labeled RNAs (RNA‐BrU) are immunoprecipitated from total RNA using anti‐BrU antibody‐coated beads. The half‐life of each transcript is calculated from the decreasing amount of RNA‐BrU measured by RNA‐seq. (b) 4sU‐seq: 4sU‐labeled RNAs (RNA‐4sU) among total RNA are biotinylated by covalently linking biotin to 4sU. Biotinylated RNA‐4sU can be isolated using streptavidin‐coated beads. RNA‐4sU is recovered by elution with reducing agent. (c) TT‐seq: TT‐seq is based on 4sU‐seq. Before isolation of RNA‐4sU, TT‐seq includes RNA fragmentation, allowing the isolation of only newly transcribed RNA‐4sU. (d) SLAM‐seq and TimeLapse‐seq: Both methods induce reverse transcription‐dependent U‐to‐C conversion in 4sU nucleotides. In both methods, 4sU is chemically converted (alkylated in SLAM‐seq and oxidized in TimeLapse‐seq and TUC‐seq), which is easily converted to C
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Schematic illustration of the strategy to identify bona‐fide targets of RBPs based on the combination of binding analysis and mRNA stability analysis. “Bona‐fide targets” of RBPs can be experimentally determined as a transcript that binds to the RBP and a transcript in which the stability is regulated by the RBP. RIP‐seq and CLIP‐seq can determine the mRNAs associated with the RBP (left) and BRIC‐seq and 4sU‐seq can measure the decay rate of mRNAs (right). Bona‐fide targets can be defined for a network module by combining these two results
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Network motifs and module in a transcriptional network. For motifs, autoregulation, multi‐component loop, feed‐forward loop (FFL), single‐input “module” (SIM), and dense overlapping regulons (DOR) are shown. Here, the TF is illustrated as a blue circle (X) and its target gene is shown as a red square (Z). Transcriptional network based on motifs and modules are also illustrated
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Schematic representation of response with different kinetics. At an initial time point, cell perturbation or stimuli induces changes in RNA synthesis and/or decay rates, resulting in modified steady‐state levels. The reference time profile is shown by the black line. To increase steady‐state levels, cells will increase synthesis (red line) or reduce decay (blue line) rates. Although both approaches increase RNA amounts, they result in different response times (time required to establish a new steady state). For a rapid response time without decreasing the fold‐change of expression level (green line in the bottom figure), cells must increase both synthesis and decay rates
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RNA Turnover and Surveillance > Regulation of RNA Stability
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA Methods > RNA Analyses In Vitro and In Silico

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