Best practices for single-cell analysis across modalities

Nature Reviews Genetics, Год журнала: 2023, Номер 24(8), С. 550 - 572

Опубликована: Март 31, 2023

Язык: Английский

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Chromatin accessibility: methods, mechanisms, and biological insights

Nucleus, Год журнала: 2022, Номер 13(1), С. 238 - 278

Опубликована: Ноя. 20, 2022

Access to DNA is a prerequisite the execution of essential cellular processes that include transcription, replication, chromosomal segregation, and repair. How proteins regulate these function in context chromatin its dynamic architectures an intensive field study. Over past decade, genome-wide assays new imaging approaches have enabled greater understanding how access genome regulated by nucleosomes associated proteins. Additional mechanisms may control accessibility vivo compaction phase separation – are beginning be understood. Here, we review ongoing development measurements, summarize different molecular structural shape landscape, detail many important biological functions linked accessibility.

Язык: Английский

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Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications

Nature Genetics, Год журнала: 2024, Номер 56(6), С. 1168 - 1180

Опубликована: Май 9, 2024

Abstract Chromatin modifications are linked with regulating patterns of gene expression, but their causal role and context-dependent impact on transcription remains unresolved. Here we develop a modular epigenome editing platform that programs nine key chromatin modifications, or combinations thereof, to precise loci in living cells. We couple this single-cell readouts systematically quantitate the magnitude heterogeneity transcriptional responses elicited by each specific modification. Among these, show installing histone H3 lysine 4 trimethylation (H3K4me3) at promoters can causally instruct hierarchically remodeling landscape. further dissect how DNA sequence motifs influence marks, identifying switch-like attenuative effects within distinct cis contexts. Finally, examine interplay combinatorial revealing co-targeted H3K27 (H3K27me3) H2AK119 monoubiquitination (H2AK119ub) maximizes silencing penetrance across single Our precision-perturbation strategy unveils principles modification(s) dissects quantitative calibrated contextual interactions.

Язык: Английский

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Energy-driven genome regulation by ATP-dependent chromatin remodellers

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 25(4), С. 309 - 332

Опубликована: Дек. 11, 2023

Язык: Английский

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New genetic and epigenetic insights into the chemokine system: the latest discoveries aiding progression toward precision medicine

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(7), С. 739 - 776

Опубликована: Май 17, 2023

Abstract Over the past thirty years, importance of chemokines and their seven-transmembrane G protein-coupled receptors (GPCRs) has been increasingly recognized. Chemokine interactions with trigger signaling pathway activity to form a network fundamental diverse immune processes, including host homeostasis responses disease. Genetic nongenetic regulation both expression structure conveys chemokine functional heterogeneity. Imbalances defects in system contribute pathogenesis variety diseases, cancer, inflammatory metabolic neurological disorders, which render focus studies aiming discover therapies important biomarkers. The integrated view biology underpinning divergence plasticity provided insights into dysfunction disease states, including, among others, coronavirus 2019 (COVID-19). In this review, by reporting latest advances results from analyses plethora sequencing-based datasets, we outline recent understanding genetic variations heterogeneity provide an updated contribution pathophysiological network, focusing on chemokine-mediated inflammation cancer. Clarification molecular basis dynamic chemokine-receptor will help advance achieve precision medicine application clinic.

Язык: Английский

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Systematic assessment of ISWI subunits shows that NURF creates local accessibility for CTCF

Nature Genetics, Год журнала: 2024, Номер 56(6), С. 1203 - 1212

Опубликована: Май 30, 2024

Abstract Catalytic activity of the imitation switch (ISWI) family remodelers is critical for nucleosomal organization and DNA binding certain transcription factors, including insulator protein CTCF. Here we define contribution individual subcomplexes by deriving a panel isogenic mouse stem cell lines, each lacking one six ISWI accessory subunits. Individual deletions subunits either CERF, RSF, ACF, WICH or NoRC only moderately affect chromatin landscape, while removal NURF-specific subunit BPTF leads to strong reduction in accessibility SNF2H ATPase localization around CTCF sites. This affects adjacent nucleosome occupancy binding. At group sites with reduced accessibility, persists but cohesin reduced, resulting decreased insulation. These results suggest that can be separated from its function as an nuclear identify specific role NURF mediating opening at bound

Язык: Английский

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ChromBPNet: bias factorized, base-resolution deep learning models of chromatin accessibility reveal cis-regulatory sequence syntax, transcription factor footprints and regulatory variants

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

Опубликована: Дек. 25, 2024

Despite extensive mapping of cis-regulatory elements (cREs) across cellular contexts with chromatin accessibility assays, the sequence syntax and genetic variants that regulate transcription factor (TF) binding at context-specific cREs remain elusive. We introduce ChromBPNet, a deep learning DNA model base-resolution profiles detects, learns deconvolves assay-specific enzyme biases from regulatory determinants accessibility, enabling robust discovery compact TF motif lexicons, cooperative precision footprints assays sequencing depths. Extensive benchmarks show despite its lightweight design, is competitive much larger contemporary models predicting variant effects on pioneer reporter activity cell ancestry, while providing interpretation disrupted syntax. ChromBPNet also helps prioritize interpret influence complex traits rare diseases, thereby powerful lens to decode variation.

Язык: Английский

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Pioneer activity distinguishes activating from non‐activating SOX2 binding sites

The EMBO Journal, Год журнала: 2023, Номер 42(20)

Опубликована: Сен. 11, 2023

Genome-wide transcriptional activity involves the binding of many transcription factors (TFs) to thousands sites in genome. Pioneer TFs are a class that maintain open chromatin and allow non-pioneer access their target sites. Determining which TF directly drive remains challenge. Here, we use acute protein depletion pioneer SOX2 establish its functionality maintaining accessibility. We show accessible lost within an hour depletion, indicating rapid turnover these absence factor. To understand relationship with transcription, performed nascent analysis found maintained by highly predictive gene expression, contrast all other CRISPR-Cas9 genome editing Klf2 locus functionally validate predicted regulatory element. conclude is exerted mainly at where it maintains accessibility largely dispensable for regulation.

Язык: Английский

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Detection of new pioneer transcription factors as cell-type-specific nucleosome binders

eLife, Год журнала: 2024, Номер 12

Опубликована: Янв. 31, 2024

Wrapping of DNA into nucleosomes restricts accessibility to and may affect the recognition binding motifs by transcription factors. A certain class factors, pioneer can specifically recognize their sites on nucleosomes, initiate local chromatin opening, facilitate co-factors in a cell-type-specific manner. For majority human locations sites, mechanisms binding, regulation remain unknown. We have developed computational method predict ability factors bind integrating ChIP-seq, MNase-seq, DNase-seq data with details nucleosome structure. demonstrated our approach discriminating from canonical predicted new potential H1, K562, HepG2, HeLa-S3 cell lines. Last, we systematically analyzed interaction modes between various detected several clusters distinctive nucleosomal DNA.

Язык: Английский

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ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF

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

Опубликована: Март 12, 2024

Summary Gene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc finger protein 143 (ZNF143/ZFP143) factor that has been implicated in both gene activation and chromatin looping. To study direct consequences ZNF143/ZFP143 loss, we generated degron line. Our results show depletion no effect on Systematic analysis occupancy data revealed commonly used antibody cross-reacts with CTCF, leading to its incorrect association loops. Nevertheless, specifically activates nuclear-encoded mitochondrial genes loss leads severe dysfunction. Using an vitro embryo model, find essential regulator organismal development. establish as conserved transcriptional cell proliferation differentiation safeguarding activity. Highlights Acute degradation ZFP143 rapid specific transcription. Molecular are inconsistent role proteins. regulation homeostasis critical for multicellular Graphical Abstract

Язык: Английский

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