Regulation of ribosomal RNA gene copy number, transcription and nucleolus organization in eukaryotes

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(6), P. 414 - 429

Published: Feb. 2, 2023

Language: Английский

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Epigenetic regulatory layers in the 3D nucleus

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(3), P. 415 - 428

Published: Jan. 18, 2024

Nearly 7 decades have elapsed since Francis Crick introduced the central dogma of molecular biology, as part his ideas on protein synthesis, setting fundamental rules sequence information transfer from DNA to RNAs and proteins. We learned that gene expression is finely tuned in time space, due activities proteins regulatory elements, through cell-type-specific three-dimensional conformations genome. Here, we review major advances genome biology discuss a set regulation highlight how various biomolecular assemblies lead formation structural features within nucleus, with roles transcriptional control. conclude by suggesting further developments will help capture complex, dynamic, often spatially restricted events govern mammalian cells.

Language: Английский

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Close to the edge: Heterochromatin at the nucleolar and nuclear peripheries

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Journal Year: 2020, Volume and Issue: 1864(1), P. 194666 - 194666

Published: Dec. 8, 2020

Language: Английский

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Genome-wide maps of nucleolus interactions reveal distinct layers of repressive chromatin domains

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

Published: March 18, 2022

Abstract Eukaryotic chromosomes are folded into hierarchical domains, forming functional compartments. Nuclear periphery and nucleolus two nuclear landmarks contributing to repressive chromosome architecture. However, while the role of lamina (NL) in genome organization has been well documented, function remains under-investigated due lack methods for identification nucleolar associated domains (NADs). Here we have established DamID- HiC-based methodologies generate accurate genome-wide maps NADs embryonic stem cells (ESCs) neural progenitor (NPCs), revealing layers compartmentalization with distinct, chromatin states based on interaction nucleolus, NL, or both. show higher H3K9me2 lower H3K27me3 content than regions exclusively interacting NL. Upon ESC differentiation NPCs, around acquire a more compact, rigid architecture genes moving away from nucleoli becoming unlocked later activation. Further, histone modifications strength within A B compartments LADs ESCs set choice associate NL upon dissociation their respective during differentiation. The here developed will make possible include contribution space diverse biological systems.

Language: Английский

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The human ribosomal DNA array is composed of highly homogenized tandem clusters

Genome Research, Journal Year: 2021, Volume and Issue: 31(11), P. 1971 - 1982

Published: Aug. 18, 2021

The structure of the human ribosomal DNA (rDNA) cluster has traditionally been hard to analyze owing its highly repetitive nature. However, recent development long-read sequencing technology, such as Oxford Nanopore sequencing, enabled us study large-scale genome. Using this we found that cells have a quite regular rDNA structure. Although each copy some variations in noncoding region, contiguous copies are similar, suggesting homogenization through gene conversion frequently occurs between copies. Analysis methylation by further showed all regions heavily methylated, whereas about half coding clearly unmethylated. ratio unmethylated copies, which speculated be transcriptionally active, was lower individuals with higher number, there is mechanism keeps active number stable. In addition, progeroid syndrome patient reduced repair activity had more unstable compared control normal cells, although rate much than previously reported using fiber-FISH method. Collectively, our results clarify view stability and transcription regulation indicating presence mechanisms for both homogenizations ensure sequence quality maintenance cellular functions.

Language: Английский

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Nuclear morphology predicts cell survival to cisplatin chemotherapy

Neoplasia, Journal Year: 2023, Volume and Issue: 42, P. 100906 - 100906

Published: May 10, 2023

The emergence of chemotherapy resistance drives cancer lethality in patients, with treatment initially reducing overall tumor burden followed by resistant recurrent disease. While molecular mechanisms underlying phenotypes have been explored, less is known about the cell biological characteristics cells that survive to eventually seed recurrence. To identify unique phenotypic associated survival upon exposure, we characterized nuclear morphology and function as prostate recovered following cisplatin treatment. Cells survived days weeks after resisted therapy-induced death showed increasing size size, enabled continuous endocycling resulting repeated whole genome doubling. We further found therapy release were predominantly mononucleated likely employ more efficient DNA damage repair. Finally, show surviving exhibit a distinct nucleolar phenotype increased rRNA levels. These data support paradigm where soon release, treated population mostly contains high level widespread catastrophic leads apoptosis, while minority successful DDR are access pro-survival state. findings consistent accession polyaneuploid (PACC) state, recently described mechanism Our demonstrate fate define key PACC This work essential for understanding and, ultimately, targeting

Language: Английский

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A mammalian model reveals inorganic polyphosphate channeling into the nucleolus and induction of a hyper-condensate state

Cell Reports Methods, Journal Year: 2024, Volume and Issue: 4(7), P. 100814 - 100814

Published: July 1, 2024

Inorganic polyphosphate (polyP) is a ubiquitous polymer that controls fundamental processes. To overcome the absence of genetically tractable mammalian model, we developed an inducible cell line expressing Escherichia coli kinase 1 (EcPPK1). Inducing EcPPK1 expression prompted polyP synthesis, enabling validation analytical methods. Virtually all newly synthesized accumulates within nucleus, mainly in nucleolus. The channeled nucleolus results redistribution its markers, leading to altered rRNA processing. Ultrastructural analysis reveals electron-dense structures associated with hyper-condensed resulting from exacerbation liquid-liquid phase separation (LLPS) phenomena controlling this membraneless organelle. selective accumulation nucleoli could be interpreted as amplification channeling where physiological function takes place. Indeed, quantitative several lines confirms endogenous

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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Nucleolus and Nucleolar Stress: From Cell Fate Decision to Disease Development

Cells, Journal Year: 2022, Volume and Issue: 11(19), P. 3017 - 3017

Published: Sept. 27, 2022

Besides the canonical function in ribosome biogenesis, there have been significant recent advances towards fascinating roles of nucleolus stress response, cell destiny decision and disease progression. Nucleolar stress, an emerging concept describing aberrant nucleolar structure as a result impaired rRNA synthesis biogenesis under conditions, has linked to variety signaling transductions, including but not limited Mdm2-p53, NF-κB HIF-1α pathways. Studies uncovered that is sensor hub when cells encounter various such nutrient deprivation, DNA damage oxidative thermal stress. Consequently, plays pivotal role determination fate, apoptosis, senescence, autophagy differentiation, response stress-induced damage. homeostasis involved pathogenesis chronic diseases, particularly tumorigenesis, neurodegenerative diseases metabolic disorders. Mechanistic insights revealed indispensable nucleolus-initiated progression these diseases. Accordingly, intervention may pave path for developing novel therapies against In this review, we systemically summarize findings linking responses, transduction cell-fate decision, set spotlight on mechanisms by which drives progression, highlight merit intervening treatment.

Language: Английский

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Molecular mechanisms of cellular metabolic homeostasis in stem cells

International Journal of Oral Science, Journal Year: 2023, Volume and Issue: 15(1)

Published: Dec. 1, 2023

Abstract Many tissues and organ systems have intrinsic regeneration capabilities that are largely driven maintained by tissue-resident stem cell populations. In recent years, growing evidence has demonstrated cellular metabolic homeostasis plays a central role in mediating fate, tissue regeneration, homeostasis. Thus, thorough understanding of the mechanisms regulate cells may contribute to our knowledge on how is provide novel insights for disease management. this review, we summarize known relationship between regulation molecular pathways cells. We also discuss potential targets therapy describe current limitations future directions development these therapeutic targets.

Language: Английский

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