Phase Separation and Correlated Motions in Motorized Genome

The Journal of Physical Chemistry B, Journal Year: 2022, Volume and Issue: 126(30), P. 5619 - 5628

Published: July 20, 2022

The human genome is arranged in the cell nucleus nonrandomly, and phase separation has been proposed as an important driving force for organization. However, active system, contribution of nonequilibrium activities to structure dynamics remains be explored. We simulated using energy function parametrized with chromosome conformation capture (Hi-C) data presence active, nondirectional forces that break detailed balance. found may arise from transcription chromatin remodeling can dramatically impact spatial localization heterochromatin. When applied euchromatin, drive heterochromatin nuclear envelope compete passive interactions among tend pull them opposite directions. Furthermore, induce long-range correlations genomic loci beyond single territories. further showed could understood effective temperature defined fluctuation-dissipation ratio. Our study suggests significantly dynamics, producing unexpected collective phenomena.

Language: Английский

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Epigenetic aging in adult neurogenesis

Hippocampus, Journal Year: 2023, Volume and Issue: 33(4), P. 347 - 359

Published: Jan. 9, 2023

Abstract Neural stem cells (NSCs) in the hippocampus generate new neurons throughout life, which functionally contribute to cognitive flexibility and mood regulation. Yet adult hippocampal neurogenesis substantially declines with age age‐related impairments NSC activity underlie this reduction. Particularly, increased quiescence consequently reduced proliferation are considered be major drivers of low levels aged brain. Epigenetic regulators control gene expression programs underlying quiescence, differentiation hence critical regulation neurogenesis. alterations have also emerged as central hallmarks aging, recent studies suggest deterioration NSC‐specific epigenetic landscape a driver age‐dependent decline In review, we summarize recently accumulating evidence for role dysregulation aging propose perspectives future research directions.

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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Actin contraction controls nuclear blebbing and rupture independent of actin confinement

Molecular Biology of the Cell, Journal Year: 2023, Volume and Issue: 35(2)

Published: Dec. 13, 2023

The nucleus is a mechanically stable compartment of the cell that contains genome and performs many essential functions. Nuclear mechanical components chromatin lamins maintain nuclear shape, compartmentalization, function by resisting antagonistic actin contraction confinement. Studies have yet to compare perturbations side-by-side as well modulated while holding confinement constant. To accomplish this, we used localization signal green fluorescent protein measure shape rupture in live cells with lamin perturbations. We then maintaining measured height. Wild type, decompaction, B1 null present bleb-based deformations ruptures dependent on independent Actin inhibition Y27632 decreased blebbing activation CN03 increased frequency. Lamin A/C results overall abnormal also reliant contraction, but similar blebs wild type. Increased DNA damage caused or which can be relieved rescues decreases levels all Thus, drives blebbing, ruptures, changes

Language: Английский

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Applications and analytical tools of cell communication based on ligand-receptor interactions at single cell level

Cell & Bioscience, Journal Year: 2021, Volume and Issue: 11(1)

Published: July 3, 2021

Cellular communication is an essential feature of multicellular organisms. Binding ligands to their homologous receptors, which activate specific cell signaling pathways, a basic type cellular and intimately linked many degeneration processes leading diseases.

Language: Английский

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Unravelling the mechanotransduction pathways in Alzheimer’s disease

Journal of Biological Engineering, Journal Year: 2023, Volume and Issue: 17(1)

Published: March 28, 2023

Abstract Alzheimer’s disease (AD) represents one of the most common and debilitating neurodegenerative disorders. By end 2040, AD patients might reach 11.2 million in USA, around 70% higher than 2022, with severe consequences on society. As now, we still need research to find effective methods treat AD. Most studies focused tau amyloid hypothesis, but many other factors are likely involved pathophysiology In this review, summarize scientific evidence dealing mechanotransduction players highlight relevant mechano-responsive elements that play a role pathophysiology. We AD-related extracellular matrix (ECM), nuclear lamina, transport synaptic activity. The literature supports ECM alteration causes lamin A increment patients, leading formation blebs invaginations. Nuclear have pore complexes, impairing nucleo-cytoplasmic transport. This may result hyperphosphorylation its consequent self-aggregation tangles, which impairs neurotransmitters It all exacerbates transmission impairment, characteristic patient’s memory loss. Here related for first time associating pathway neurons. addition, highlighted entire influencing diseases, paving way new perspectives context pathologies.

Language: Английский

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Perturbations in 3D genome organization can promote acquired drug resistance

Cell Reports, Journal Year: 2023, Volume and Issue: 42(10), P. 113124 - 113124

Published: Sept. 20, 2023

Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 cells can acquire to Taxol by derepressing ABCB1 gene, encoding for multidrug transporter P-gP. Here, we investigate how gene derepressed. activation associated with reduced H3K9 trimethylation, increased H3K27 acetylation, and displacement from nuclear lamina. While altering DNA methylation had no impact on expression, nor did it promote resistance, disrupting lamina component Lamin B Receptor acquisition Taxol-resistant phenotype subset cells. CRISPRa-mediated supported notion that dissociation influences derepression. We propose model which repressed allows its activation, implying deregulation 3D genome topology could play an important role tumor evolution resistance.

Language: Английский

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At the nucleus of cancer: how the nuclear envelope controls tumor progression

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 24, 2025

Abstract Historically considered downstream effects of tumorigenesis—arising from changes in DNA content or chromatin organization—nuclear alterations have long been seen as mere prognostic markers within a genome‐centric model cancer. However, recent findings placed the nuclear envelope (NE) at forefront tumor progression, highlighting its active role mediating cellular responses to mechanical forces. Despite significant progress, precise interplay between NE components and cancer progression remains under debate. In this review, we provide comprehensive up‐to‐date overview how composition affect mechanics facilitate malignant transformation, grounded latest molecular functional studies. We also review research that uses advanced technologies, including artificial intelligence, predict malignancy risk treatment outcomes by analyzing morphology. Finally, discuss progress understanding has paved way for mechanotherapy—a promising approach exploits differences cancerous healthy cells. Shifting perspective on diagnostic potential therapeutic targets, calls further investigation into evolving cancer, innovative strategies transform conventional therapies.

Language: Английский

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Fam170a deficiency causes male infertility by impairing histone-to-protamine exchange during mouse spermiogenesis

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(3)

Published: Jan. 24, 2025

Abstract Chromatin remodeling, which involves the histone-to-protamine exchange process during spermiogenesis, is crucial for sperm nuclear condensation and male fertility. However, key regulators underlying molecular mechanisms involved in this remain largely unexplored. In study, we discovered that deficiency family with sequence similarity 170 member A (Fam170a) led to abnormal morphology infertility mice, mirroring observation of very low Fam170a transcription levels infertile men teratozoospermia. Further investigation revealed plays a significant role chromatin remodeling process. This was evidenced by earlier core histone removal, accelerated translation degradation transition proteins, reduced protamine incorporation spermiogenesis Fam170a-deleted mice. Mechanistically, found interacts remodeling-associated proteins regulates genes related remodeling. Notably, directly deubiquitinating enzyme Usp7 facilitates its translocation elongating sperm, enhancing activity on testis-specific H2A H2B variants. Collectively, our findings identify as previously unrecognized regulator suggest deubiquitination may play an essential

Language: Английский

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Lamin B1 regulates RNA splicing factor expression by modulating the spatial positioning and chromatin interactions of the ETS1 gene locus

Animal Cells and Systems, Journal Year: 2025, Volume and Issue: 29(1), P. 149 - 162

Published: Feb. 15, 2025

Lamin B1, a crucial component of the nuclear lamina, plays pivotal role in chromatin organization and transcriptional regulation eukaryotic cells. While recent studies have highlighted connection between B1 RNA splicing regulation, precise molecular mechanisms remain elusive. In this study, we demonstrate that depletion leads to global reduction factor expression, as evidenced by analysis multiple RNA-seq datasets. Motif suggests members ETS transcription family likely bind promoter regions these factors. Further using databases ChIP-seq data identified ETS1 key regulator expression. Hi-C sequencing revealed loss disrupts inter-LAD interactions near gene locus, resulting its downregulation. These findings suggest indirectly regulates sustaining proper uncovering novel link architecture, splicing.

Language: Английский

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