Emergent microenvironments of nucleoli

Nucleus, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 5, 2024

In higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The prominent coexisting are fibrillar center (FC), dense component (DFC), and granular (GC). Here, we review recent efforts in profiling sub-phase compositions shed light on types of physicochemical properties emerge from compositional biases territorial organization specific macromolecules. We highlight roles played by molecular grammars which refers to protein sequence features substrate binding domains, intrinsically disordered regions, multivalence these distinct domains / regions. introduce concept a barcode emergent nucleoli. Although our knowledge full remains incomplete, hope prompts investigations into undiscovered engenders an appreciation for how why unique microenvironments control biochemical reactions

Language: Английский

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Cell type–specific 3D-genome organization and transcription regulation in the brain

Science Advances, Journal Year: 2025, Volume and Issue: 11(9)

Published: Feb. 26, 2025

3D organization of the genome plays a critical role in regulating gene expression. How 3D-genome differs among different cell types and relates to type–dependent transcriptional regulation remains unclear. Here, we used genome-scale DNA RNA imaging investigate transcriptionally distinct mouse cerebral cortex. We uncovered wide spectrum differences nuclear architecture types, ranging from size nucleus higher-order chromosome structures radial positioning chromatin loci within nucleus. These variations exhibit strong correlations with both total activity type–specific marker genes. Moreover, found that methylated binding protein MeCP2 promotes active-inactive segregation regulates transcription position–dependent manner is highly correlated its function modulating compartmentalization.

Language: Английский

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dcHiC detects differential compartments across multiple Hi-C datasets

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 11, 2022

The compartmental organization of mammalian genomes and its changes play important roles in distinct biological processes. Here, we introduce dcHiC, which utilizes a multivariate distance measure to identify significant compartmentalization among multiple contact maps. Evaluating dcHiC on four collections bulk single-cell maps from vitro mouse neural differentiation (n = 3), hematopoiesis 10), human LCLs 20) post-natal brain development 3 stages), show effectiveness sensitivity detecting biologically relevant changes, including those orthogonally validated. reported regions with dynamically regulated genes associated cell identity, along correlated chromatin states, subcompartments, replication timing lamin association. With efficient implementation, enables high-resolution compartment analysis as well standalone browser visualization, differential interaction identification time-series clustering. is an essential addition the Hi-C toolbox for ever-growing number Available at: https://github.com/ay-lab/dcHiC .

Language: Английский

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Nucleolar-based Dux repression is essential for embryonic two-cell stage exit

Genes & Development, Journal Year: 2022, Volume and Issue: 36(5-6), P. 331 - 347

Published: March 1, 2022

Upon fertilization, the mammalian embryo must switch from dependence on maternal transcripts to transcribing its own genome, and in mice this involves transient up-regulation of MERVL transposons MERVL-driven genes at two-cell stage. The mechanisms requirement for (2C) gene are poorly understood. Moreover, transcriptional program be rapidly shut off allow exit developmental progression. Here, we report that robust ribosomal RNA (rRNA) synthesis nucleolar maturation essential 2C state. 2C-like cells embryos show similar immature nucleoli with altered structure reduced rRNA output. We reveal disruption via blocking polymerase I activity or preventing phase separation enhances conversion a state embryonic stem (ESCs) by detachment activator Dux surface. In embryos, prevents proper silencing leads two- four-cell arrest. Our findings an intriguing link between synthesis, maturation, repression during early development.

Language: Английский

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Mapping nucleolus-associated chromatin interactions using nucleolus Hi-C reveals pattern of heterochromatin interactions

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 21, 2023

Abstract As the largest substructures in nucleus, nucleoli are sites of ribosome biogenesis. Increasing evidence indicates that play a key role organization 3D genome architecture, but systematic studies nucleolus-associated chromatin interactions lacking. Here, we developed nucleolus Hi-C (nHi-C) experimental technique to enrich interactions. Using nHi-C experiment, identify 264 high-confidence domains (hNADs) form strong heterochromatin associated with and consist 24% whole HeLa cells. Based on global hNAD inter-chromosomal interactions, find five nucleolar organizer region (NOR)-bearing chromosomes formed into two clusters show different interaction patterns, which is concordant their epigenetic states gene expression levels. hNADs can be divided three groups display distinct cis / trans signals, frequencies nucleoli, distance from centromeres, overlap percentage lamina-associated (LADs). Nucleolus disassembly caused by Actinomycin D (ActD) significantly decreases strength affects compartment/TAD genome-wide. In summary, our results provide view organized around demonstrate act as an inactive hub shape both compartments TADs.

Language: Английский

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DNA replication in early mammalian embryos is patterned, predisposing lamina-associated regions to fragility

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 19, 2024

Abstract DNA replication in differentiated cells follows a defined program, but when and how it is established during mammalian development not known. Here we show using single-cell sequencing, that late replicating regions are association with the B compartment nuclear lamina from first cell cycle after fertilization on both maternal paternal genomes. Late contain relative paucity of active origins few long genes low G/C content. In bovine mouse embryos, timing patterns prior to embryonic genome activation. Chromosome breaks, which form spontaneously embryos at sites concordant human preferentially locate regions. mice, enhanced fragility due sparsity dormant can be activated under conditions stress. This pattern predisposes neuronal genetic change separation soma germ lineages. Our studies segregation early among layers organization fertilization.

Language: Английский

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rRNA biogenesis regulates mouse 2C-like state by 3D structure reorganization of peri-nucleolar heterochromatin

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Nov. 9, 2021

Abstract The nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. However, its role in regulating stem cell fate remains unclear. Here, we present evidence that nucleolar stress induced by interfering rRNA can drive 2-cell stage embryo-like (2C-like) program induce an expanded 2C-like population mouse embryonic (mES) cells. Mechanistically, integrity maintains normal liquid-liquid phase separation (LLPS) formation peri-nucleolar heterochromatin (PNH). Upon defects biogenesis, natural state LLPS disrupted, causing dissociation NCL/TRIM28 complex from PNH changes epigenetic reorganization 3D structure PNH, which leads to release Dux, a 2C transcription factor, activate program. Correspondingly, embryos with defect are unable develop (2C) 4-cell embryos, delayed repression 2C/ERV genes transcriptome skewed toward earlier cleavage embryo signatures. Our results highlight rRNA-mediated reshaping compartment regulates transition mES cells cells, critical regulator during murine pre-implantation development.

Language: Английский

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3D genome, on repeat: Higher-order folding principles of the heterochromatinized repetitive genome

Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2690 - 2707

Published: July 1, 2022

Language: Английский

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Nucleoli and the nucleoli–centromere association are dynamic during normal development and in cancer

Molecular Biology of the Cell, Journal Year: 2023, Volume and Issue: 34(4)

Published: Feb. 8, 2023

In this study, the authors show nucleoli and centromeres interact dynamically not only during normal differentiation across a variety of cellular models including myocytes, keratinocytes, neurons, but in cancer cells as well. Differentiation leads to decrease association between nucleoli, with exhibiting an increased frequency more typical proliferative cells.

Language: Английский

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Choreography of lamina‐associated domains: structure meets dynamics

FEBS Letters, Journal Year: 2023, Volume and Issue: 597(22), P. 2806 - 2822

Published: Nov. 1, 2023

Lamina‐associated domains are large regions of heterochromatin positioned at the nuclear periphery. These have been implicated in gene repression, especially context development. In mammals, LAD organization is dependent on lamins, inner membrane proteins, and chromatin state. addition, readers modifier proteins this organization, potentially serving as molecular tethers that interact with both envelope chromatin. More recent studies focused teasing apart rules govern dynamic how turn, relates to regulation overall 3D genome organization. This review highlights mammalian cells uncovering factors instruct choreography re‐organization, dynamics lamina, including interphase through mitotic exit, when re‐established, well intra‐LAD subdomain variations.

Language: Английский

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