The total mRNA concentration buffering system in yeast is global rather than gene-specific

Garcı́a-Martı́nez, José; Medina, Daniel A.; Bellvís, Pablo; Sun, Mai; Cramer, Patrick; Pérez‐Ortín, José E.

doi:10.1101/2021.01.14.426689

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…However, it is unclear if this compensatory behavior is pervasive in other genes, species, and contexts. While some studies have indicated the absence of this kind of compensation in organisms such as yeast 25,26 , to date, no genome-wide investigation of this behavior has been undertaken for different mammalian cell types and contexts. As a result, several questions remain unanswered.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

Mellis

Bodkin²,

Goyal³

2023

Preprint

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Cells and tissues have a remarkable ability to adapt to genetic perturbations via a variety of molecular mechanisms. Nonsense-induced transcriptional compensation, a form of transcriptional adaptation, has recently emerged as one such mechanism, in which nonsense mutations in a gene can trigger upregulation of related genes, possibly conferring robustness at cellular and organismal levels. However, beyond a handful of developmental contexts and curated sets of genes, to date, no comprehensive genome-wide investigation of this behavior has been undertaken for mammalian cell types and contexts. Moreover, how the regulatory-level effects of inherently stochastic compensatory gene networks contribute to phenotypic penetrance in single cells remains unclear. Here we combine computational analysis of existing datasets with stochastic mathematical modeling and machine learning to uncover the widespread prevalence of transcriptional adaptation in mammalian systems and the diverse single-cell manifestations of minimal compensatory gene networks. Regulon gene expression analysis of a pooled single-cell genetic perturbation dataset recapitulates our model predictions. Our integrative approach uncovers several putative hits-genes demonstrating possible transcriptional adaptation-to follow up on experimentally, and provides a formal quantitative framework to test and refine models of transcriptional adaptation.

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Section: Introductionmentioning

confidence: 99%

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

Mellis

Bodkin²,

Goyal³

2023

Preprint

View full text Add to dashboard Cite

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The NELF pausing checkpoint mediates the functional divergence of Cdk9

et al. 2023

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Promoter-proximal pausing by RNA Pol II is a rate-determining step in gene transcription that is hypothesized to be a prominent point at which regulatory factors act. The pausing factor NELF is known to induce and stabilize pausing, but not all kinds of pausing are NELF-mediated. Here, we find that NELF-depleted Drosophila melanogaster cells functionally recapitulate the NELF-independent pausing we previously observed in fission yeast (which lack NELF). Critically, only NELF-mediated pausing establishes a strict requirement for Cdk9 kinase activity for the release of paused Pol II into productive elongation. Upon inhibition of Cdk9, cells with NELF efficiently shutdown gene transcription, while in NELF-depleted cells, defective, non-productive transcription continues unabated. By introducing a strict checkpoint for Cdk9, the evolution of NELF was likely critical to enable increased regulation of Cdk9 in higher eukaryotes, as Cdk9 availability can be restricted to limit gene transcription without inducing wasteful, non-productive transcription.

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Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

Mellis,

Melzer,

Bodkin

et al. 2024

Genome Biol

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Background Cells and tissues have a remarkable ability to adapt to genetic perturbations via a variety of molecular mechanisms. Nonsense-induced transcriptional compensation, a form of transcriptional adaptation, has recently emerged as one such mechanism, in which nonsense mutations in a gene trigger upregulation of related genes, possibly conferring robustness at cellular and organismal levels. However, beyond a handful of developmental contexts and curated sets of genes, no comprehensive genome-wide investigation of this behavior has been undertaken for mammalian cell types and conditions. How the regulatory-level effects of inherently stochastic compensatory gene networks contribute to phenotypic penetrance in single cells remains unclear. Results We analyze existing bulk and single-cell transcriptomic datasets to uncover the prevalence of transcriptional adaptation in mammalian systems across diverse contexts and cell types. We perform regulon gene expression analyses of transcription factor target sets in both bulk and pooled single-cell genetic perturbation datasets. Our results reveal greater robustness in expression of regulons of transcription factors exhibiting transcriptional adaptation compared to those of transcription factors that do not. Stochastic mathematical modeling of minimal compensatory gene networks qualitatively recapitulates several aspects of transcriptional adaptation, including paralog upregulation and robustness to mutation. Combined with machine learning analysis of network features of interest, our framework offers potential explanations for which regulatory steps are most important for transcriptional adaptation. Conclusions Our integrative approach identifies several putative hits—genes demonstrating possible transcriptional adaptation—to follow-up on experimentally and provides a formal quantitative framework to test and refine models of transcriptional adaptation. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-024-03351-2.

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The total mRNA concentration buffering system in yeast is global rather than gene-specific

Cited by 3 publications

References 41 publications

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

The NELF pausing checkpoint mediates the functional divergence of Cdk9

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

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