Modulation of cellular processes by histone and non-histone protein acetylation

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 23(5), С. 329 - 349

Опубликована: Янв. 18, 2022

Язык: Английский

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Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

Molecular Cell, Год журнала: 2021, Номер 81(10), С. 2183 - 2200.e13

Опубликована: Май 1, 2021

To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic transcriptomic analyses following acute inhibition major cellular lysine acetyltransferases P300 CBP in hematological malignancies. We found that catalytic P300/CBP dynamically perturbs steady-state kinetics suppresses oncogenic networks the absence changes to accessibility. CRISPR-Cas9 screening identified NCOR1 HDAC3 co-repressors as principal antagonists by counteracting turnover kinetics. Finally, deacetylation H3K27 provides nucleation sites for reciprocal methylation switching, a feature can be exploited therapeutically concomitant KDM6A inhibition. Overall, this study indicates acetylation-methylation equilibrium functions molecular rheostat governing transcription is amenable therapeutic exploitation an anti-cancer regimen.

Язык: Английский

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3D enhancer-promoter interactions and multi-connected hubs: Organizational principles and functional roles

Cell Reports, Год журнала: 2023, Номер 42(4), С. 112068 - 112068

Опубликована: Апрель 1, 2023

The spatiotemporal control of gene expression is dependent on the activity cis-acting regulatory sequences, called enhancers, which regulate target genes over variable genomic distances and, often, by skipping intermediate promoters, suggesting mechanisms that enhancer-promoter communication. Recent genomics and imaging technologies have revealed highly complex interaction networks, whereas advanced functional studies started interrogating forces behind physical communication among multiple enhancers promoters. In this review, we first summarize our current understanding factors involved in communication, with a particular focus recent papers new layers complexities to old questions. second part subset connected "hubs" discuss their potential functions signal integration regulation, as well putative might determine dynamics assembly.

Язык: Английский

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Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project

Molecular Cell, Год журнала: 2023, Номер 83(15), С. 2624 - 2640

Опубликована: Июль 6, 2023

Язык: Английский

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Heritable transcriptional defects from aberrations of nuclear architecture

Nature, Год журнала: 2023, Номер 619(7968), С. 184 - 192

Опубликована: Июнь 7, 2023

Abstract Transcriptional heterogeneity due to plasticity of the epigenetic state chromatin contributes tumour evolution, metastasis and drug resistance 1–3 . However, mechanisms that cause this variation are incompletely understood. Here we identify micronuclei chromosome bridges, aberrations in nucleus common cancer 4,5 , as sources heritable transcriptional suppression. Using a combination approaches, including long-term live-cell imaging same-cell single-cell RNA sequencing (Look-Seq2), identified reductions gene expression chromosomes from micronuclei. With heterogeneous penetrance, these changes can be even after micronucleus has been re-incorporated into normal daughter cell nucleus. Concomitantly, micronuclear acquire aberrant marks. These defects may persist variably reduced accessibility clonal expansion single cells. Persistent repression is strongly associated with, explained by, markedly long-lived DNA damage. Epigenetic alterations transcription therefore inherently coupled chromosomal instability nuclear architecture.

Язык: Английский

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RNA polymerase II is required for spatial chromatin reorganization following exit from mitosis

Science Advances, Год журнала: 2021, Номер 7(43)

Опубликована: Окт. 22, 2021

Following exit from mitosis, RNA Pol II is required for reestablishing 3D genome folding by loading cohesin complexes onto DNA.

Язык: Английский

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CTCF and transcription influence chromatin structure re-configuration after mitosis

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Авг. 27, 2021

During mitosis, transcription is globally attenuated and chromatin architecture dramatically reconfigured. We exploited the M- to G1-phase progression interrogate contributions of architectural factor CTCF process genome re-sculpting in newborn nuclei. Depletion during transition alters short-range compartmentalization after mitosis. Chromatin domain boundary re-formation impaired upon loss, but a subset boundaries, characterized by transitions states, established normally. Without CTCF, structural loops fail form, leading illegitimate contacts between cis-regulatory elements (CREs). Transient CRE that are normally resolved telophase persist deeply into CTCF-depleted cells. loss-associated gains often linked increased, enhancer-promoter contacts. In contrast, at genes whose expression declines seems function as conventional activator, independent its role. CTCF-anchored facilitate formation nested within them, especially those involving weak CREs. Transcription inhibition does not significantly affect global or start site-associated boundaries. However, ongoing contributes considerably gene domains, regions enriched along bodies. Notably, domains emerge ana/telophase prior completion first round transcription, suggesting epigenetic features bodies contribute reconfiguration transcription. The focus on de novo nuclear G1 entry yields insights dynamics mitosis progression.

Язык: Английский

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Anopheles mosquitoes reveal new principles of 3D genome organization in insects

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Апрель 12, 2022

Chromosomes are hierarchically folded within cell nuclei into territories, domains and subdomains, but the functional importance evolutionary dynamics of these hierarchies poorly defined. Here, we comprehensively profile genome organizations five Anopheles mosquito species show how different levels chromatin architecture influence each other. Patterns observed on Hi-C maps associated with known cytological structures, epigenetic profiles, gene expression levels. Evolutionary analysis reveals conservation synteny blocks for tens millions years enrichment breakpoints in regions increased genomic insulation. However, in-depth shows a confounding effect density both insulation distribution breakpoints, suggesting limited causal relationship between At level individual loci, identify specific, extremely long-ranged looping interactions, conserved ~100 million years. We demonstrate that mechanisms underlying contacts differ from previously described Polycomb-dependent interactions clustering active chromatin.

Язык: Английский

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Mitotic bookmarking by SWI/SNF subunits

Nature, Год журнала: 2023, Номер 618(7963), С. 180 - 187

Опубликована: Май 24, 2023

Язык: Английский

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Epigenetic mechanisms to propagate histone acetylation by p300/CBP

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 17, 2023

Histone acetylation is important for the activation of gene transcription but little known about its direct read/write mechanisms. Here, we report cryogenic electron microscopy structures in which a p300/CREB-binding protein (CBP) multidomain monomer recognizes histone H4 N-terminal tail (NT) (ac) nucleosome and acetylates non-H4 NTs within same nucleosome. p300/CBP not only recognized H4NTac via bromodomain pocket responsible reading, also interacted with DNA minor grooves outside that pocket. This directed catalytic center to one NTs. The primary target p300 writes by reading was H2BNT, H2BNTac promoted H2A-H2B dissociation from We propose model replicates H3-H4 tetramer inherit epigenetic storage, transcribes it H2B-H2A dimers activate context-dependent through local destabilization.

Язык: Английский

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