Transcriptional precision and accuracy in development: from measurements to models and mechanisms

Bentovim, Lital; Harden, Timothy T.; DePace, Angela H.

doi:10.1242/dev.146563

Cited by 35 publications

(33 citation statements)

References 171 publications

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“…Predictions with this model on a large-scale basis, however, are far from perfect (Segal et al, 2008). As experimental tools are becoming more sophisticated, complex relationships between TF binding sequences, TF occupancy, and transcript abundance are being found, thus suggesting that sequence-controlled TF occupancy may not directly convert into transcription rate (Spitz and Furlong, 2012;Bentovim et al, 2017). For example, in two Drosophila species, Khoueiry et al (2017) found conserved combinatorial TF occupancy despite sequence divergence, and conserved enhancer function despite diverged occupancy.…”

Section: Discussionmentioning

confidence: 99%

Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation

Cesbron

Oehler

et al. 2018

Cell Systems

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Gene regulation is a complex non-equilibrium process. Here, we show that quantitating the temporal regulation of key gene states (transcriptionally inactive, active, and refractory) provides a parsimonious framework for analyzing gene regulation. Our theory makes two non-intuitive predictions. First, for transcription factors (TFs) that regulate transcription burst frequency, as opposed to amplitude or duration, weak TF binding is sufficient to elicit strong transcriptional responses. Second, refractoriness of a gene after a transcription burst enables rapid responses to stimuli. We validate both predictions experimentally by exploiting the natural, optogenetic-like responsiveness of the Neurospora GATA-type TF White Collar Complex (WCC) to blue light. Further, we demonstrate that differential regulation of WCC target genes is caused by different gene activation rates, not different TF occupancy, and that these rates are tuned by both the core promoter and the distance between TF-binding site and core promoter. In total, our work demonstrates the relevance of a kinetic, non-equilibrium framework for understanding transcriptional regulation.

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Section: Discussionmentioning

confidence: 99%

Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation

Cesbron

Oehler

et al. 2018

Cell Systems

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“…In the case of Tbx1/10 and Ebf , spatially and temporally accurate activation is essential to permit the emergence of first and second cardiac, and pharyngeal muscle lineages 14,15,17,43 . We propose that, whereas the activity of multiple elements with similar spatio-temporal transcriptional outputs permits precise and robust gene activation 67,79 , the modular organization of the cis -regulatory system increases the repertoire of regulatory inputs, acting through both accessibility and activity, to control cell-specific gene expression. These multi-level combinatorial inputs achieve exquisite spatio-temporal control, while permitting strong activation, thus ensuring both transcriptional precision and accuracy for developmental fate choices (Fig.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

Racioppi

Wiechecki

Christiaen

2019

Preprint

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In embryos, lineage-specific profiles of chromatin accessibility control gene expression by modulating transcription, and thus impact multipotent progenitor states and subsequent fate choices. Subsets of cardiac and pharyngeal/head muscles share a common origin in the cardiopharyngeal mesoderm, but the chromatin landscapes that govern multipotent progenitors’ competence and early fate choices remain largely elusive. Here, we leveraged the simplicity of the chordate model Ciona to profile chromatin accessibility through stereotyped transitions from naive Mesp+ mesoderm to distinct fate-restricted heart and pharyngeal muscle precursors. An FGF-Foxf pathway acts in multipotent progenitors to establish cardiopharyngeal-specific patterns of accessibility, which govern later heart vs. pharyngeal muscle-specific expression profiles, demonstrating extensive spatiotemporal decoupling between early cardiopharyngeal enhancer accessibility and late cell-type-specific activity. Combinations of cis-regulatory elements with distinct chromatin accessibility profiles are required to activate of Ebf and Tbx1/10, two key determinants of cardiopharyngeal fate choices. We propose that this higher order combinatorial logic increases the repertoire of regulatory inputs that control gene expression, through either accessibility and/or activity, thus fostering spatially and temporally accurate fate choices.

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“…These attempts range from modeling a monotone gradient (Gregor et al, 2007), to quantifying variation in gene expression patterns Fowlkes et al, 2008;Knowles, 2012;Martinez-Abadias et al, 2018). To our knowledge, however, very few (Bentovim et al, 2017;Park et al, 2019) used comprehensive descriptors to thoroughly extract more information than possible from qualitative approaches, or exploited the statistical power offered by such descriptors. This prompted us to implement a generic quantitative framework to measure and compare activity levels of the spot 196 enhancer across the wing among genotypes, and use powerful statistical tools to test the significance of the differences.…”

Section: Quantitative Assessment Of Gene Expression To Decipher Regulmentioning

confidence: 99%

Deciphering the regulatory logic of aDrosophilaenhancer through systematic sequence mutagenesis and quantitative image analysis

Poul

Xin

Ling

et al. 2020

Preprint

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Transcriptional enhancers are short DNA sequences controlling the spatial activity, timing and levels of eukaryotic gene transcription. Their quantitative transcriptional output is thought to result from the number and organization of transcription factor binding sites (TFBSs). Yet, how the various aspects of regulatory information are encoded in enhancer sequences remains elusive. We addressed this question by quantifying the spatial activity of the yellow spot enhancer active in developing Drosophila wings. To identify which enhancer DNA sequence contributes to enhancer activity, we introduced systematic mutations along the enhancer. We developed an analytic framework that uses comprehensive descriptors to quantify reporter assay in transgenic Deciphering the regulatory logic of an enhancer 2 flies and measure spatial variations in activity levels across the wing. Our analysis highlights an unexpected density of regulatory information in the spot enhancer sequence. Furthermore, it reveals an unanticipated regulatory logic underlying the activity of this enhancer, and how it reads the wing trans-regulatory landscape to encode a spatial pattern.Deciphering the regulatory logic of an enhancer

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Transcriptional precision and accuracy in development: from measurements to models and mechanisms

Cited by 35 publications

References 171 publications

Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation

Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

Deciphering the regulatory logic of aDrosophilaenhancer through systematic sequence mutagenesis and quantitative image analysis

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