A foundation model of transcription across human cell types

Nature, Год журнала: 2025, Номер 637(8047), С. 965 - 973

Опубликована: Янв. 8, 2025

Transcriptional regulation, which involves a complex interplay between regulatory sequences and proteins, directs all biological processes. Computational models of transcription lack generalizability to accurately extrapolate unseen cell types conditions. Here we introduce GET (general expression transformer), an interpretable foundation model designed uncover grammars across 213 human fetal adult types1,2. Relying exclusively on chromatin accessibility data sequence information, achieves experimental-level accuracy in predicting gene even previously types3. also shows remarkable adaptability new sequencing platforms assays, enabling inference broad range conditions, uncovers universal cell-type-specific factor interaction networks. We evaluated its performance prediction activity, elements regulators, identification physical interactions factors found that it outperforms current models4 lentivirus-based massively parallel reporter assay readout5,6. In erythroblasts7, identified distal (greater than 1 Mbp) regions were missed by previous models, and, B cells, lymphocyte-specific factor-transcription explains the functional significance leukaemia risk predisposing germline mutation8-10. sum, provide generalizable accurate for together with catalogues regulation interactions, type specificity.

Язык: Английский

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Single-molecule chromatin configurations link transcription factor binding to expression in human cells

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

Опубликована: Фев. 4, 2024

The binding of multiple transcription factors (TFs) to genomic enhancers activates gene expression in mammalian cells. However, the molecular details that link enhancer sequence TF binding, promoter state, and levels remain opaque. We applied single-molecule footprinting (SMF) measure simultaneous occupancy TFs, nucleosomes, components machinery on engineered enhancer/promoter constructs with variable numbers sites for both a synthetic an endogenous TF. find activation domains enhance TF's capacity compete nucleosomes DNA BAF-dependent manner, nucleosome-free is consistent independent between average linearly contributes rates. also decompose strength into separable terms, which can be tuned perturbed independently. Finally, we develop thermodynamic kinetic models quantitatively predict microstates observed at subsequent time-dependent expression. This work provides template quantitative dissection distinct contributors activation, including activity chromatin remodelers, domains, acetylation, concentration, affinity, site configuration.

Язык: Английский

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Transcription regulation by biomolecular condensates

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 8, 2024

Язык: Английский

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Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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High-throughput affinity measurements of direct interactions between activation domains and co-activators

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

Опубликована: Авг. 20, 2024

Abstract Sequence-specific activation by transcription factors is essential for gene regulation 1,2 . Key to this are domains, which often fall within disordered regions of 3,4 and recruit co-activators initiate 5 These interactions difficult characterize via most experimental techniques because they typically weak transient 6,7 Consequently, we know very little about whether these promiscuous or specific, the mechanisms binding, how tune strength activation. To address questions, developed a microfluidic platform expression purification hundreds domains in parallel followed direct measurement co-activator binding affinities (STAMMPPING, Simultaneous Trapping Affinity Measurements Microfluidic Protein-Protein INteraction Generator). By applying STAMMPPING quantify between eight 204 human (>1,500 K d s), provide first quantitative map reveal 334 novel pairs. We find that metazoan-specific P300 directly binds >100 potentially explaining its widespread recruitment across genome influence transcriptional Despite sharing similar molecular properties ( e.g. enrichment negative hydrophobic residues), utilize distinct biophysical certain domains. Co-activator domain affinity occupancy well-predicted analytical models account multivalency, vitro quantitatively predict cells with an ultrasensitive response. Not only do our results demonstrate ability measure even protein-protein high throughput, but also necessary resource over 1,500 domain/co-activator lays foundation understanding basis

Язык: Английский

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p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer

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

Опубликована: Март 30, 2024

Prostate cancer is an exemplar of enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. paralog lysine acetyltransferases p300 CBP deposit histone marks that are associated with activation. Here, we demonstrate p300/CBP determinant cofactors the active AR in prostate cancer. Histone H2B N-terminus multisite acetylation (H2BNTac), which exclusively reliant on catalytic function, marked enhancers was notably elevated lesions relative adjacent benign epithelia. Degradation rapidly depleted enhanceosome, only partially phenocopied by inhibition their reader bromodomains. Notably, H2BNTac effectively abrogated upon degradation, led a stronger suppression p300/CBP-dependent oncogenic gene programs bromodomain or its domain.

Язык: Английский

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Single-molecule analysis of transcription activation: dynamics of SAGA coactivator recruitment

Nature Structural & Molecular Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

Язык: Английский

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Basic Epigenetic Mechanisms

Sub-cellular biochemistry/Subcellular biochemistry, Год журнала: 2025, Номер unknown, С. 1 - 49

Опубликована: Янв. 1, 2025

Язык: Английский

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Transcription and epigenetic factor dynamics in neuronal activity-dependent gene regulation

Trends in Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Chromatin landscape at cis-regulatory elements orchestrates cell fate decisions in early embryogenesis

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

Опубликована: Март 27, 2025

Abstract The establishment of germ layers during early development is crucial for body formation. Drosophila zygote serves as a model investigating these transitions in relation to the chromatin landscape. However, cellular heterogeneity blastoderm embryo poses challenge gaining mechanistic insights. Using 10× Multiome, we simultaneously analyzed vivo epigenomic and transcriptomic states wild-type, E(z)-, CBP-depleted embryos zygotic genome activation at single-cell resolution. We found that pre-zygotic H3K27me3 safeguards tissue-specific gene expression by modulating cis -regulatory elements. Furthermore, demonstrate CBP essential cell fate specification functioning transcriptional activator stabilizing factors binding key developmental genes. Surprisingly, while depletion leads arrest, accessibility continues progress independently through retention stalled RNA Polymerase II. Our study reveals fundamental principles chromatin-mediated regulation establishing maintaining identities embryogenesis.

Язык: Английский

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