Phase Separation and Correlated Motions in Motorized Genome

The Journal of Physical Chemistry B, Год журнала: 2022, Номер 126(30), С. 5619 - 5628

Опубликована: Июль 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.

Язык: Английский

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Epigenetic aging in adult neurogenesis

Hippocampus, Год журнала: 2023, Номер 33(4), С. 347 - 359

Опубликована: Янв. 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.

Язык: Английский

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Choreography of lamina‐associated domains: structure meets dynamics

FEBS Letters, Год журнала: 2023, Номер 597(22), С. 2806 - 2822

Опубликована: Ноя. 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.

Язык: Английский

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Actin contraction controls nuclear blebbing and rupture independent of actin confinement

Molecular Biology of the Cell, Год журнала: 2023, Номер 35(2)

Опубликована: Дек. 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

Язык: Английский

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

Cell & Bioscience, Год журнала: 2021, Номер 11(1)

Опубликована: Июль 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.

Язык: Английский

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Unravelling the mechanotransduction pathways in Alzheimer’s disease

Journal of Biological Engineering, Год журнала: 2023, Номер 17(1)

Опубликована: Март 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.

Язык: Английский

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Perturbations in 3D genome organization can promote acquired drug resistance

Cell Reports, Год журнала: 2023, Номер 42(10), С. 113124 - 113124

Опубликована: Сен. 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.

Язык: Английский

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The nexus of nuclear envelope dynamics, circular economy and cancer cell pathophysiology

European Journal of Cell Biology, Год журнала: 2024, Номер 103(2), С. 151394 - 151394

Опубликована: Фев. 6, 2024

The nuclear envelope (NE) is a critical component in maintaining the function and structure of eukaryotic nucleus. NE lamina are disassembled during each cell cycle to enable an open mitosis. Nuclear architecture construction deconstruction prime example circular economy, as it fulfills highly efficient recycling program bound continuous assessment quality functionality building blocks. Alterations dynamics have emerged important contributors both oncogenic transformation cancer progression. However, knowledge breakdown reassembly still limited fraction participating proteins complexes. As cells contain diverse nuclei terms DNA content, but also number, size, shape, great interest understand intricate relationship between these features pathophysiology. In this review, we provide insights into how those regulated, destabilization processes may alter economy. Moreover, expand lamina-associated domain region by using strategic algorithms, including Artificial Intelligence, infer protein associations, assess their location, predict cancer-type specificity with implications for future diagnosis, prognosis treatment. Using approach identified NUP98 MECP2 potential that exhibit upregulation Acute Myeloid Leukemia (LAML) patients early diagnosis.

Язык: Английский

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Imaging analysis of six human histone H1 variants reveals universal enrichment of H1.2, H1.3, and H1.5 at the nuclear periphery and nucleolar H1X presence

eLife, Год журнала: 2024, Номер 12

Опубликована: Март 26, 2024

Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential distribution of repertoire human through imaging techniques including super-resolution microscopy. variants exhibit characteristic patterns both interphase mitosis. H1.2, H1.3, H1.5 are universally enriched at periphery all cell lines analyzed co-localize with compacted DNA. H1.0 shows a less pronounced peripheral localization, apparent variability among different lines. On other hand, H1.4 H1X distributed throughout nucleus, being high-GC regions abundant nucleoli. Interestingly, show more lacking H1.3 H1.5. The suggest specific functionalities organizing lamina-associated domains or nucleolar activity, which further supported by distinct response phosphorylated inhibition ribosomal DNA transcription. Moreover, depletion affects structure variant-specific manner. Concretely, H1.2 knock-down, either alone combined, triggers global decompaction. Overall, has allowed us distinguish beyond segregation two groups denoted previous ChIP-Seq determinations. Our results support that functionality can be shared between types.

Язык: Английский

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Multilevel view on chromatin architecture alterations in cancer

Frontiers in Genetics, Год журнала: 2022, Номер 13

Опубликована: Ноя. 18, 2022

Chromosomes inside the nucleus are not located in form of linear molecules. Instead, there is a complex multilevel genome folding that includes nucleosomes packaging, formation chromatin loops, domains, compartments, and finally, chromosomal territories. Proper spatial organization play an essential role for correct functioning genome, therefore dynamically changed during development or disease. Here we discuss how cancer cell differs from healthy at various levels. A better understanding malignization affects long-range gene regulation will help to reveal molecular mechanisms underlying evolution.

Язык: Английский

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