Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease

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

Published: Jan. 22, 2024

Abstract Whilst it is recognised that targeting self-renewal an effective way to functionally impair the quiescent leukaemic stem cells (LSC) persist as residual disease in chronic myeloid leukaemia (CML), developing therapeutic strategies achieve this have proved challenging. We demonstrate regulatory programmes of LSC phase CML are similar embryonic cells, pointing a role for wild type p53 self-renewal. In support this, increasing activity primitive using MDM2 inhibitor combination with tyrosine kinase resulted reduced CFC outputs and engraftment potential, followed by loss multilineage priming potential exhaustion when treatment was discontinued. Our work provides evidence exploitable clinic irreversibly function – enable more patients discontinue therapy remain therapy-free remission.

Language: Английский

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Tfap2b specifies an embryonic melanocyte stem cell that retains adult multifate potential

Cell Reports, Journal Year: 2022, Volume and Issue: 38(2), P. 110234 - 110234

Published: Jan. 1, 2022

Melanocytes, the pigment-producing cells, are replenished from multiple stem cell niches in adult tissue. Although pigmentation traits known risk factors for melanoma, we know little about melanocyte (McSC) populations other than hair follicle McSCs and lack key lineage markers with which to identify study their function. Here find that Tfap2b a select set of target genes specify an McSC population at dorsal root ganglia zebrafish. Functionally, is required only few late-stage embryonic melanocytes, essential McSC-dependent regeneration. Fate mapping data reveal tfap2b+ have multifate potential, cells origin large patches two pigment types (iridophores xanthophores), nerve-associated cells. Hence, confers identity early development, distinguishing neural crest lineages, retains potential

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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Phase Separation: Direct and Indirect Driving Force for High-Order Chromatin Organization

Genes, Journal Year: 2023, Volume and Issue: 14(2), P. 499 - 499

Published: Feb. 15, 2023

The multi-level spatial chromatin organization in the nucleus is closely related to activity. mechanism of and remodeling attract much attention. Phase separation describes biomolecular condensation which basis for membraneless compartments cells. Recent research shows that phase a key aspect drive high-order structure remodeling. In addition, functional compartmentalization formed by also plays an important role overall structure. this review, we summarized latest work about organization, focusing on direct indirect effects 3D its impact transcription regulation.

Language: Английский

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METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation

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

Published: Aug. 21, 2024

Abstract Nucleoli are fundamentally essential sites for ribosome biogenesis in cells and formed by liquid-liquid phase separation (LLPS) a multilayer condensate structure. How the nucleoli integrity is maintained remains poorly understood. Here, we reveal that METTL3/METTL14, typical methyltransferase complex catalyzing N6-methyladnosine (m 6 A) on mRNAs maintain human embryonic stem (hESCs). METTL3/METTL14 deficiency impairs leads to complete loss of self-renewal hESCs. We further show SUV39H1/H2 protein, methyltransferases H3K9me3 were dramatically elevated deficient cells, which causes an accumulation infiltration across whole nucleolus LLPS. Mechanistically, serves as adapter CRL4 E3 ubiquitin ligase targeting polyubiquitination proteasomal degradation therefore prevents nucleoli. Together, these findings uncover previously unknown role facilitating cells.

Language: Английский

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Molecular Mechanisms of Plant Regeneration from Differentiated Cells: Approaches from Historical Tissue Culture Systems

Plant and Cell Physiology, Journal Year: 2022, Volume and Issue: 64(3), P. 297 - 304

Published: Dec. 22, 2022

Abstract Plants can exert remarkable capacity for cell reprogramming even from differentiated cells. This ability allows plants to regenerate tissues/organs and individuals in nature vitro. In recent decades, Arabidopsis research has uncovered molecular mechanisms of plant regeneration; however, our understanding how cells retain both status developmental plasticity is still obscure. this review, we first provide a brief outlook the representative modes regeneration key factors revealed by research. We then re-examine historical tissue culture systems that enable us investigate details discuss different approaches, specifically highlighting progress shoot epidermal Torenia fournieri.

Language: Английский

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Differential contributions of nuclear lamina association and genome compartmentalization to gene regulation

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

Published: April 5, 2023

Chromatin regions that interact with the nuclear lamina are often heterochromatic, repressed in gene expression, and spatial B compartment. However, exceptions to this trend allow us examine relative impact of lamin association compartment on regulation. Here, we compared association, Hi-C, histone mark datasets from cell lines representing different states differentiation across cell-type lineages. With these data, compare, for example, expression differences when a region is associated one type but not another. In general, observed an additive rather than redundant effect status. But, whether status or had dominant influence varied by type. Finally, identified how likelihood induction repression response physicochemical treatment.

Language: Английский

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Pollution induces epigenetic effects that are stably transmitted across multiple generations

Evolution Letters, Journal Year: 2022, Volume and Issue: 6(2), P. 118 - 135

Published: Feb. 4, 2022

It has been hypothesized that the effects of pollutants on phenotypes can be passed to subsequent generations through epigenetic inheritance, affecting populations long after removal a pollutant. But there is still little evidence induce persistent in animals. Here, we show low doses commonly used genome-wide differences cytosine methylation freshwater crustacean Daphnia pulex. Uniclonal were either continually exposed or switched clean water, and was compared control did not experience pollutant exposure. Although some direct changes only present populations, others both water treatments, suggesting these modifications had persisted for 7 months (>15 generations). We also identified indicating long-term legacy exposure distinct from effects. Pollutant-induced differential tended occur at sites highly methylated controls. Modifications observed treatments controls showed reduced treatments. On other hand, found just treatment have lower levels increase treatment. In second experiment, confirmed sublethal same generate life histories least three following Our results demonstrate even transgenerational are stably transmitted over many generations. Persistent likely influence phenotypic development, which could contribute rapid adaptation, extinction, confronted by anthropogenic stressors.

Language: Английский

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Mechanism Analysis of LINC00665 and Its Peptides CIP2A-BP in Hepatocellular Carcinoma

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: March 8, 2022

Background: More and more studies show that long non-coding RNAs (lncRNAs) have miniature open reading frames can be translated into short peptides. Here, we identify the gene LINC00665 its peptides (CIP2A-BP) in hepatocellular carcinoma (HCC) explore how they contribute to HCC progression. Materials methods: First, GSE101728 data were acquired through Gene Expression Omnibus for identification of differentially expressed genes (DEGs), set enrichment analysis (GSEA) was conducted find enriched biological pathways. Then, further bioinformatics carried out on screened genes, expression detected normal liver samples. The relations between expression, prognosis, clinical characteristics studied. Receiver operating characteristic (ROC) also applied verify prediction prognosis. In addition, pertinent experiments CIP2A-BP their roles progression HCC. Results: As a result, 332 DEGs total, including 130 upregulated 202 downregulated DEGs. These mainly posttranscriptional regulation RNA processing, nucleolus, silencing found increased samples, which substantially indicated poor Compared with tissues, had higher pathological stages III IV, tumor-free groups, people no than 60 years old, T3, T4, N0, N1, M1. ROC curve variable INC00665 certain accuracy predicting overall survival (OS). Moreover, functional experiments, knockdown could significantly decrease cell proliferation, migration, invasion, while overexpressed markedly increase migration. Conclusion: Our findings not only disclose unique mechanism by encoded promotes carcinogenesis but suggest these used as biomarkers diagnosis prognosis new targets therapy.

Language: Английский

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Nucleolar structure connects with global nuclear organization

Molecular Biology of the Cell, Journal Year: 2023, Volume and Issue: 34(12)

Published: Aug. 23, 2023

The nucleolus is a multifunctional nuclear body. To tease out the roles of nucleolar structure without resorting to use multi-action drugs, we knocked down RNA polymerase I subunit RPA194 in HeLa cells by siRNA. Loss resulted nucleolar-structural segregation and effects on both nucleolus-proximal distal-nuclear components. perinucleolar compartment was disrupted, centromere clustering around nucleoli significantly reduced, intranuclear locations specific genomic loci were altered. Moreover, Cajal bodies, distal from nucleoli, underwent morphological some compositional changes. In comparison, when preribosomal RNA-processing factor, UTP4, down, neither nor observed, demonstrating that changes proximal domains knockdown unlikely arise cessation ribosome synthesis, rather consequence nucleolar-structure alteration. These findings point commutative system links maintenance spatial organization certain loci.

Language: Английский

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