Bridging spatial and temporal scales of developmental gene regulation

Current Opinion in Genetics & Development, Год журнала: 2025, Номер 92, С. 102328 - 102328

Опубликована: Март 12, 2025

The development of multicellular organisms relies on the precise coordination molecular events across multiple spatial and temporal scales. Understanding how information flows from interactions to cellular processes tissue organization during is crucial for explaining remarkable reproducibility complex organisms. This review explores chromatin-encoded transduced localized transcriptional global gene expression patterns, highlighting challenge bridging these We discuss recent experimental findings theoretical frameworks, emphasizing polymer physics as a tool describing relationship between chromatin structure dynamics By integrating perspectives, we aim clarify regulation coordinated levels biological suggest strategies future approaches.

Язык: Английский

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Chromatin structure and dynamics: one nucleosome at a time

Histochemistry and Cell Biology, Год журнала: 2024, Номер 162(1-2), С. 79 - 90

Опубликована: Апрель 12, 2024

Язык: Английский

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Reshaping transcription and translation dynamics during the awakening of the zygotic genome

Current Opinion in Genetics & Development, Год журнала: 2025, Номер 92, С. 102344 - 102344

Опубликована: Апрель 7, 2025

During the oocyte-to-embryo transition, transcriptome and proteome are dramatically reshaped. This transition entails a shift from maternally inherited mRNAs to newly synthesized transcripts, produced during zygotic genome activation (ZGA). Furthermore, crucial transcription translation selectivity is required for early embryonic development. Studies across various model organisms have revealed conserved cis- trans-regulatory mechanisms dictating regimes by which mRNA proteins this critical phase. In article, we highlight recent technological conceptual advances that deepen our understanding of how tuning both evolves ZGA.

Язык: Английский

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Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 20, 2023

Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds subjects millions cells. These studies promise to give unprecedented insight into the cell type specific biology human disease. Yet performing differential expression analyses across remains difficult due challenges statistical modeling these complex scaling large datasets. Our open-source R package dreamlet (DiseaseNeurogenomics.github.io/dreamlet) uses a pseudobulk approach based on precision-weighted linear mixed models identify genes differentially expressed with traits for each cluster. Designed data cohorts, is substantially faster less memory than existing workflows, while supporting controlling false positive rate. We demonstrate computational performance published datasets, novel dataset 1.4M single nuclei postmortem brains 150 Alzheimer's disease cases 149 controls.

Язык: Английский

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Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA

Current Opinion in Structural Biology, Год журнала: 2024, Номер 88, С. 102875 - 102875

Опубликована: Июль 10, 2024

Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal to gain access or employ alternative DNA-binding modes with smaller footprints, they preferentially solvent-exposed near entry/exit sites, and frequently interact histones. The extent of TF-histone interactions, turn, depends on motif location nucleosome, type fold, adjacent domains present. interactions phase TF relative nucleosomes, we discuss how these complex surprisingly diverse between nucleosomes contribute function.

Язык: Английский

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Establishment and maintenance of random monoallelic expression

Development, Год журнала: 2024, Номер 151(10)

Опубликована: Май 15, 2024

ABSTRACT This Review elucidates the regulatory principles of random monoallelic expression by focusing on two well-studied examples: X-chromosome inactivation regulator Xist and olfactory receptor gene family. Although choice a single X chromosome or occurs in different developmental contexts, common guide both systems. In cases, an event breaks symmetry between genetically epigenetically identical copies gene, leading to one allele, stabilized through negative feedback control. many steps that govern establishment maintenance have been identified, key pieces puzzle are still missing. We provide overview current knowledge models for receptors. discuss their similarities differences, highlight open questions approaches could study other monoallelically expressed genes.

Язык: Английский

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Mouse promoters are characterised by low occupancy and high turnover of RNA polymerase II

Molecular Systems Biology, Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

Abstract The general transcription machinery and its occupancy at promoters are highly conserved across metazoans. This contrasts with the kinetics of mRNA production that considerably differ between model species such as Drosophila mouse. molecular basis for these kinetic differences is currently unknown. Here, we used Single-Molecule Footprinting to measure RNA Polymerase II (Pol II) occupancy, fraction DNA molecules bound, in mouse cell lines. Single-molecule data reveals Pol on average 3–5 times more frequent transcriptionally active than promoters. Kinetic modelling states suggests determined by ratio initiation turnover rates. We chemical perturbation determine rate both species. Integration into shows infrequent explained combination high low

Язык: Английский

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Dynamic modes of Notch transcription hubs conferring memory and stochastic activation revealed by live imaging the co-activator Mastermind

eLife, Год журнала: 2023, Номер 12

Опубликована: Окт. 31, 2023

Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The relay in Notch pathway relies on nuclear complexes containing co-activator Mastermind (Mam). By tracking these real time, we reveal that they promote formation a dynamic transcription hub ON nuclei which concentrates key factors including Mediator CDK module. composition is labile persists after withdrawal conferring memory enables rapid reformation. Surprisingly, only third hubs progress state with nascent transcription, correlates polymerase II core recruitment. This probability increased by second signal. discovery target-gene probabilistic has far-reaching implications because it implies stochastic differences output can arise downstream receptor activation.

Язык: Английский

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Cooperativity among clustered κB sites within promoters and enhancers dictates transcriptional specificity of NF-κB RelA along with specific cofactors

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

Опубликована: Июль 3, 2024

ABSTRACT The functional role of weak DNA binding sites for transcription factor (TF) recruitment and gene expression remains largely unknown. Our study reveals that the NF-κB sites, which are abundant in promoters enhancers, appear clusters exhibit minimal to undetectable activity isolation vitro, yet they play prominent roles regulation within native context cells. We found nuclear concentration RelA/p65, predominant NF-κB, is approximately 0.2 µM stimulated cells, challenging idea these κB operate through mass action-dependent mechanisms. Through proteomic analysis, we identified a range factors, including various other TFs, interacting with RelA at κB-sites. ChIP-seq, RNA-seq phase-separated condensation analyses suggest additional referred as cofactors facilitate dynamic clustered specific target genes. Overall, our findings demonstrate collective contribution both strong occupancy facilitated by variety cofactors. This congregation multiple factors forming larger complexes appearing condensate likely be common all transcriptional programs.

Язык: Английский

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How Transcription Factors Binding Stimulates Transcriptional Bursting

The Journal of Physical Chemistry Letters, Год журнала: 2024, Номер 15(34), С. 8781 - 8789

Опубликована: Авг. 20, 2024

Transcription is a fundamental biological process of transferring genetic information which often occurs in stochastic bursts when periods intense activity alternate with quiescent phases. Recent experiments identified strong correlations between the association transcription factors (TFs) to gene promoters on DNA and transcriptional activity. However, underlying molecular mechanisms this phenomenon remain not well understood. Here, we present theoretical framework that allowed us investigate how binding dynamics TF influences bursting. Our minimal model incorporates most relevant physical-chemical features, including exchange among multiple sites at association/dissociation dynamics. Using analytical calculations supported by Monte Carlo computer simulations, it demonstrated bursting depends strength number sites. Stronger affinity prolongs burst duration but reduces variability, while an optimal maximizes noise, facilitating cellular adaptation. method explains available experimental observations quantitatively, confirming model's predictive accuracy. This study provides important insights into expression regulation, offering new tool for understanding complex processes.

Язык: Английский

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