Power-law behavior of transcriptional bursting regulated by enhancer–promoter communication

Genome Research, Год журнала: 2024, Номер 34(1), С. 106 - 118

Опубликована: Янв. 1, 2024

Revealing how transcriptional bursting kinetics are genomically encoded is challenging because genome structures stochastic at the organization level and suggestively linked to gene transcription. To address this challenge, we develop a generic theoretical framework that integrates chromatin dynamics, enhancer–promoter (E-P) communication, gene-state switching study bursting. The theory predicts power law can be general rule quantitatively describe modulations by E-P spatial communication. Specifically, burst frequency size up-regulated communication strength, following laws with positive exponents. Analysis of scaling exponents further reveals preferentially regulated. Bursting down-regulated genomic distance negative power-law exponents, modulation desensitizes large distances. mutual information between (or size) essential characteristics transfer from kinetics. These findings, which in agreement experimental observations, not only reveal fundamental principles but also for understanding cellular decision-making.

Язык: Английский

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Transient power-law behaviour following induction distinguishes between competing models of stochastic gene expression

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 22, 2025

Abstract What features of transcription can be learnt by fitting mathematical models gene expression to mRNA count data? Given a suite models, data selects an optimal one, thus identifying probable transcriptional mechanism. Whilst attractive, the utility this methodology remains unclear. Here, we sample steady-state, single-cell distributions from parameters in physiological range, and show they cannot used confidently estimate number inactive states, i.e. rate-limiting steps initiation. Distributions over 99% parameter space generated using with 2, 3, or 4 states well fit one single state. However, that for many minutes following induction, eukaryotic cells increase mean obeys power law whose exponent equals sum visited initial active state post-transcriptional processing steps. Our study shows estimation sufficient determine lower bound on total regulatory initiation, splicing, nuclear export.

Язык: Английский

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Solving stochastic gene-expression models using queueing theory: A tutorial review

Biophysical Journal, Год журнала: 2024, Номер 123(9), С. 1034 - 1057

Опубликована: Апрель 9, 2024

Stochastic models of gene expression are typically formulated using the chemical master equation, which can be solved exactly or approximately a repertoire analytical methods. Here, we provide tutorial review an alternative approach based on queueing theory that has rarely been used in literature expression. We discuss interpretation six types infinite-server queues from angle stochastic single-cell biology and expressions for stationary nonstationary distributions and/or moments mRNA/protein numbers bounds Fano factor. This may enable solution complex have hitherto evaded solution.

Язык: Английский

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Single gene analysis in yeast suggests nonequilibrium regulatory dynamics for transcription

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 23, 2024

Abstract Fluctuations in the initiation rate of transcription, first step gene expression, ensue from stochastic behavior molecular process that controls transcription. In steady state, regulatory is often assumed to operate reversibly, i.e., equilibrium. However, reversibility imposes fundamental limits information processing. For instance, assumption equilibrium difficult square with precision which executes its task eukaryotes. Here we provide evidence — microscopic analyses transcription dynamics at a single copy yeast for cyclic and irreversible (out equilibrium). The necessary coupling reservoirs free energy occurs via sequence-specific transcriptional activators recruitment, part, ATP-dependent chromatin remodelers. Our findings may help explain how eukaryotic cells reconcile dual but opposing requirements fast kinetics high specificity.

Язык: Английский

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RASP: Optimal Single Puncta Detection in Complex Cellular Backgrounds

The Journal of Physical Chemistry B, Год журнала: 2024, Номер 128(15), С. 3585 - 3597

Опубликована: Апрель 9, 2024

Super-resolution and single-molecule microscopies have been increasingly applied to complex biological systems. A major challenge of these approaches is that fluorescent puncta must be detected in the low signal, high noise, heterogeneous background environments cells tissue. We present RASP, Radiality Analysis Single Puncta, a bioimaging-segmentation method solves this problem. RASP removes false-positive other analysis methods detect detects features over broad range spatial scales: from single proteins cell phenotypes. outperforms state-of-the-art precision speed using image gradients separate Gaussian-shaped objects background. demonstrate RASP's power by showing it can extract correlations between microglia, neurons, α-synuclein oligomers human brain. This sensitive, computationally efficient approach enables cellular distinguished tissue environments, with sensitivity down level protein. Python MATLAB codes, enabling users perform on their own data, are provided as Supporting Information links third-party repositories.

Язык: Английский

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Joint distribution of nuclear and cytoplasmic mRNA levels in stochastic models of gene expression: analytical results and parameter inference

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 30, 2024

Common stochastic models of gene expression predict the analytical distribution total mRNA level per cell but not at subcellular resolution. Here, for a wide class transcription initiation, we obtain an exact steady-state solution joint nuclear and cytoplasmic levels cell. Correcting extrinsic noise fitting to single human data, precisely quantify extent bursty in thousands genes associate it with their biological functions.

Язык: Английский

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ATP6V1B1 regulates ovarian cancer progression and cisplatin sensitivity through the mTOR/autophagy pathway

Molecular and Cellular Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Май 12, 2024

Abstract Early detection and effective chemotherapy for ovarian cancer, a serious gynecological malignancy, require further progress. This study aimed to investigate the molecular mechanism of ATPase H + -Transporting V1 Subunit B1 (ATP6V1B1) in cancer development chemoresistance. Our data show that ATP6V1B1 is upregulated correlated with decreased progression-free survival. Gain- loss-of-function experiments demonstrated promotes proliferation, migration, invasion cells vitro, while knockout inhibits tumor growth vivo. In addition, knocking down increases sensitivity cisplatin. Mechanistic studies showed regulates activation mTOR/autophagy pathway. Overall, our confirmed oncogenic role revealed progression via axis.

Язык: Английский

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Deterministic patterns in single-cell transcriptomic data

npj Systems Biology and Applications, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 11, 2025

Abstract We report the existence of deterministic patterns in statistical plots single-cell transcriptomic data. develop a theory showing that are neither artifacts introduced by measurement process nor due to underlying biological mechanisms. Rather they naturally emerge from finite sample size effects. The precisely predicts data multiplexed error-robust fluorescence situ hybridization and five different types sequencing platforms.

Язык: Английский

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Incorporating spatial diffusion into models of bursty stochastic transcription

Journal of The Royal Society Interface, Год журнала: 2025, Номер 22(225)

Опубликована: Апрель 1, 2025

The dynamics of gene expression are stochastic and spatial at the molecular scale, with messenger RNA (mRNA) transcribed specific nuclear locations then transported to boundary for export. Consequently, distributions these molecules encode their underlying dynamics. While mechanistic models counts have revealed numerous insights into expression, they largely neglected now-available subcellular resolution down individual molecules. Owing technical challenges inherent in processes, tools studying patterns still limited. Here, we introduce a model mRNA two-state (telegraph) transcriptional Observations can be concisely described as following Cox process driven by stochastically switching partial differential equation. We derive analytical solutions demographic moments validate them simulations. show that distribution accurately approximated Poisson-beta tractable parameters, even complex This observation allows efficient parameter inference demonstrated on synthetic data. Altogether, our work adds progress towards new frontier inferring from static snapshot

Язык: Английский

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Cell-cycle dependence of bursty gene expression: insights from fitting mechanistic models to single-cell RNA-seq data

Nucleic Acids Research, Год журнала: 2025, Номер 53(7)

Опубликована: Март 31, 2025

Bursty gene expression is characterized by two intuitive parameters, burst frequency and size, the cell-cycle dependence of which has not been extensively profiled at transcriptome level. In this study, we estimate parameters per allele in G1 G2/M phases for thousands mouse genes fitting mechanistic models to messenger RNA count data, obtained sequencing single cells whose position inferred using a deep-learning method. We find that upon DNA replication, median approximately halves, while size remains mostly unchanged. Genome-wide distributions parameter ratios between are broad, indicating substantial heterogeneity transcriptional regulation. also observe significant negative correlation ratios, suggesting regulatory processes do independently control parameters. show accurately must explicitly account copy number variation extrinsic noise due coupling transcription cell age across cycle, but corrections technical imperfect capture molecules experiments less critical.

Язык: Английский

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