Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation

Li, Congxin; Cesbron, François; Oehler, Michael; Brunner, Michael; Höfer, Thomas

doi:10.1016/j.cels.2018.01.012

Cited by 81 publications

(103 citation statements)

References 61 publications

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“…Also, the number of CCNA2 copies actively expressing in a cell do not reflect on the overall mRNA count in that cell-there can be cells with very high mRNA count but fewer than two copies actively expressing and vice versa. This demonstrates the stochastic nature of transcriptional bursts and gene regulation via the modulation of burst frequency [38]. This might also suggest a possible decoupling between the activities of different alleles within a nucleus where each is agnostic of others' transcriptional status unlike as reported recently for the bacterial system [39].…”

Section: Discussionsupporting

confidence: 63%

Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle

Dhuppar

Mazumder

2019

Preprint

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Number of figures: 4 Number of characters in the title: 81 Number of words in abstract: 177 Number of words excluding Abstract, Materials and Methods and References: 2498 Number of references: 39 Number of supplementary movies: 1 Number of supplementary Figures: 1 Number of supplementary tables: 1 Abstract Nuclear architecture is the organization of the genome within a cell nucleus with respect to different nuclear landmarks such as nuclear lamina, matrix or nucleoli. Lately it has emerged as a major regulator of gene expression in mammalian cells. The studies connecting nuclear architecture with gene expression are largely population-averaged and do not report on the heterogeneity in genome organization or in gene expression within a population. In this report we present a method for combining 3D DNA Fluorescence in situ Hybridization (FISH) with single molecule RNA FISH (smFISH) and immunofluorescence to study nuclear architecture-dependent gene regulation on a cell-by-cell basis. We further combine it with an imaging-based cell cycle staging to correlate nuclear architecture with gene expression across the cell cycle. We present this in the context of Cyclin A2 (CCNA2) gene for its known cell cycle-dependent expression. We show that, across the cell cycle, the expression of a CCNA2 gene copy is stochastic and depends neither on its sub-nuclear position-which usually lies close to nuclear lamina-nor on the expression from the other copies. Keywords Cell cycle, 3D nuclear architecture, central dogma, DNA FISH, smFISH, Cyclin A2, nuclear lamina, immunofluorescence AM, SD conceived and designed the study. SD performed the experiments and the analysis.AM, SD interpreted the data and wrote the manuscript. AM monitored the project and associated grants. Competing interestsNone.

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Section: Discussionsupporting

confidence: 63%

Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle

Dhuppar

Mazumder

2019

Preprint

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“…TGF‐β1 stimulation, in contrast, led to a sustained increase in burst sizes. Frequency modulation has been demonstrated for c‐fos dependent transcription after serum or zinc induction (Senecal et al , ), light‐controlled transcription by the White Collar Complex in Neurospora (Li et al , ), and dose‐dependent transcriptional regulation by ligand‐bound steroid receptors (Larson et al , ). Using targeted perturbations, it has further been shown that frequency modulation and polymerase pause release are key regulatory aspects of transcriptional regulation, while RNAP2 recruitment occurs subsequent to burst initiation (Bartman et al , ).…”

Section: Discussionmentioning

confidence: 99%

Stochastic transcription in the p53‐mediated response to DNA damage is modulated by burst frequency

Friedrich

Friedel

Finzel

et al. 2019

Molecular Systems Biology

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Discontinuous transcription has been described for different mammalian cell lines and numerous promoters. However, our knowledge of how the activity of individual promoters is adjusted by dynamic signaling inputs from transcription factors is limited. To address this question, we characterized the activity of selected target genes that are regulated by pulsatile accumulation of the tumor suppressor p53 in response to ionizing radiation. We performed time‐resolved measurements of gene expression at the single‐cell level by smFISH and used the resulting data to inform a mathematical model of promoter activity. We found that p53 target promoters are regulated by frequency modulation of stochastic bursting and can be grouped along three archetypes of gene expression. The occurrence of these archetypes cannot solely be explained by nuclear p53 abundance or promoter binding of total p53. Instead, we provide evidence that the time‐varying acetylation state of p53's C‐terminal lysine residues is critical for gene‐specific regulation of stochastic bursting.

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“…Frequency modulation of target gene expression has previously been demonstrated for other cellular processes such as c-fos dependent transcription after serum or zinc induction (Senecal et al, 2014), light-controlled transcription by the White Collar Complex (WCC) in Neurospora (Li et al, 2018) and dose-dependent transcriptional regulation by ligand-bound steroid receptors . Using targeted perturbations it has further been shown that frequency modulation and polymerase pause release are key-regulatory aspects of transcriptional regulation, while RNAP2 recruitment occurs subsequent to burst initiation (Bartman et al, 2019).…”

Section: The K370/382 Methylation-acetylation Switch Contributes To Tmentioning

confidence: 99%

Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency

Friedrich

Friedel

Herrmann

et al. 2019

Preprint

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KEYWORDScellular heterogeneity/ DNA damage/ p53 signaling/ single-cell analysis/ stochastic transcription/ ABSTRACT Discontinuous transcription has been described for different mammalian cell lines and numerous promoters. However, our knowledge of how the activity of individual promoters is adjusted by dynamic signaling inputs from transcription factor is limited. To address this question, we characterized the activity of selected target genes that are regulated by pulsatile accumulation of the tumor suppressor p53 in response to ionizing radiation. We performed time resolved measurements of gene expression at the single cell level by smFISH and used the resulting data to inform a mathematical model of promoter activity. We found that p53 target promoters are regulated by frequency modulation of stochastic bursting and can be grouped along three archetypes of gene expression. The occurrence of these archetypes cannot solely be explained by nuclear p53 abundance or promoter binding of total p53. Instead, we provide evidence that the time-varying acetylation state of p53's C-terminal lysine residues is critical for gene-specific regulation of stochastic bursting. of 1 37

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Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation

Cited by 81 publications

References 61 publications

Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle

Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle

Stochastic transcription in the p53‐mediated response to DNA damage is modulated by burst frequency

Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency

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