Lamin B1 depletion in senescent cells leads to large-scale changes in the chromatin landscape
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE36641 | GEO | 2013/09/09
SECONDARY ACCESSION(S): PRJNA153643
REPOSITORIES: GEO
Similar Datasets
Project description:Lamin B1 depletion in senescent cells leads to large-scale changes in the chromatin landscape
| PRJNA153643 | ENA
Project description:Cellular senescence is a stable proliferation arrest in response to stress, associated with an altered secretory pathway (Senescence Associated Secretory Phenotype (SASP)). Senescence-associated proliferation arrest and the SASP are thought to act in concert to promote tumor suppression and tissue aging. While chromatin regulation and down regulation of lamin B1 have been implicated as effectors of cell senescence, functional interactions between them are poorly understood. We compared the genome-wide distributions of H3K4me3 and H3K27me3 between proliferating and senescent primary human cells and found dramatic differences, including large-scale domains of H3K4me3- and H3K27me3-enriched “mesas” and H3K27me3-depleted “canyons” in senescent cells. Senescent mesas form at the sites of lamin B1-associated domains (LADs) in proliferating cells. Mesas also overlap with regions that exhibit DNA hypomethylation in cancer, suggesting that chromatin changes in pre-malignant senescent cells foreshadow epigenetic changes in cancer. Proliferating fibroblasts from Hutchinson-Gilford Progeria Syndrome patients expressing mutant lamin A (progerin) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence and tissue aging. In contrast, canyons form mostly in between LADs and are enriched in genes, gene promoters and enhancers. Strikingly, H3K27me3 loss in canyons is correlated with upregulation of key senescence genes, including genes comprising the SASP, indicating a link between global changes in chromatin structure and local regulation of gene expression. Finally, premature reduction of lamin B1 in midlife proliferating cells triggers formation of senescence-associated mesas and canyons and accelerated senescence. Together, our data illustrate a profound reorganization of chromatin during senescence, and suggest that down regulation of lamin B1 in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging and cancer.
2013-09-09 | GSE36640 | GEO
Project description:Cellular senescence is a stable proliferation arrest in response to stress, associated with an altered secretory pathway (Senescence Associated Secretory Phenotype (SASP)). Senescence-associated proliferation arrest and the SASP are thought to act in concert to promote tumor suppression and tissue aging. While chromatin regulation and down regulation of lamin B1 have been implicated as effectors of cell senescence, functional interactions between them are poorly understood. We compared the genome-wide distributions of H3K4me3 and H3K27me3 between proliferating and senescent primary human cells and found dramatic differences, including large-scale domains of H3K4me3- and H3K27me3-enriched "mesas" and H3K27me3-depleted "canyons" in senescent cells. Senescent mesas form at the sites of lamin B1-associated domains (LADs) in proliferating cells. Mesas also overlap with regions that exhibit DNA hypomethylation in cancer, suggesting that chromatin changes in pre-malignant senescent cells foreshadow epigenetic changes in cancer. Proliferating fibroblasts from Hutchinson-Gilford Progeria Syndrome patients expressing mutant lamin A (progerin) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence and tissue aging. In contrast, canyons form mostly in between LADs and are enriched in genes, gene promoters and enhancers. Strikingly, H3K27me3 loss in canyons is correlated with upregulation of key senescence genes, including genes comprising the SASP, indicating a link between global changes in chromatin structure and local regulation of gene expression. Finally, premature reduction of lamin B1 in midlife proliferating cells triggers formation of senescence-associated mesas and canyons and accelerated senescence. Together, our data illustrate a profound reorganization of chromatin during senescence, and suggest that down regulation of lamin B1 in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging and cancer.
2013-09-09 | GSE36616 | GEO
Project description:Nuclear lamins play important roles in the organization and structure of the nucleus; however, the specific mechanisms linking lamin structure to nuclear functions are poorly defined. We demonstrate that reducing nuclear lamin B1 expression by short hairpin RNA-mediated silencing in cancer cell lines to approximately 50% of normal levels causes a delay in the cell cycle and accumulation of cells in early S phase. The S phase delay appears to be due to the stalling and collapse of replication forks. The double-strand DNA breaks resulting from replication fork collapse were inefficiently repaired, causing persistent DNA damage signaling and the assembly of extensive repair foci on chromatin. The expression of multiple factors involved in DNA replication and repair by both nonhomologous end joining and homologous repair is misregulated when lamin B1 levels are reduced. We further demonstrate that lamin B1 interacts directly with the promoters of some genes associated with DNA damage response and repair, including BRCA1 and RAD51. Taken together, the results suggest that the maintenance of lamin B1 levels is required for DNA replication and repair through regulation of the expression of key factors involved in these essential nuclear functions.
| S-EPMC4323489 | biostudies-literature
Project description:Peripheral heterochromatin positioning depends on nuclear envelope associated proteins and repressive histone modifications. Here we show that overexpression (OE) of Lamin B1 (LmnB1) leads to the redistribution of peripheral heterochromatin into heterochromatic foci within the nucleoplasm. These changes represent a perturbation of heterochromatin binding at the nuclear periphery (NP) through a mechanism independent from altering other heterochromatin anchors or histone post-translational modifications. We further show that LmnB1 OE alters gene expression. These changes do not correlate with different levels of H3K9me3, but a significant number of the misregulated genes were likely mislocalized away from the NP upon LmnB1 OE. We also observed an enrichment of developmental processes amongst the upregulated genes. ~74% of these genes were normally repressed in our cell type, suggesting that LmnB1 OE promotes gene de-repression. This demonstrates a broader consequence of LmnB1 OE on cell fate, and highlights the importance of maintaining proper levels of LmnB1.
| S-EPMC10114975 | biostudies-literature
Project description:Modifications in nuclear structures of cells are implicated in several diseases including cancer. They result in changes in nuclear activity, structural dynamics and cell signalling. However, the role of the nuclear lamina and related proteins in malignant melanoma is still unknown. Its molecular characterisation might lead to a deeper understanding and the development of new therapy approaches. In this study, we analysed the functional effects of dysregulated nuclear lamin B1 (LMNB1) and its nuclear receptor (LBR). According to their cellular localisation and function, we revealed that these genes are crucially involved in nuclear processes like chromatin organisation. RNA sequencing and differential gene expression analysis after knockdown of LMNB1 and LBR revealed their implication in important cellular processes driving ER stress leading to senescence and changes in chromatin state, which were also experimentally validated. We determined that melanoma cells need both molecules independently to prevent senescence. Hence, downregulation of both molecules in a BRAFV600E melanocytic senescence model as well as in etoposide-treated melanoma cells indicates both as potential senescence markers in melanoma. Our findings suggest that LMNB1 and LBR influence senescence and affect nuclear processes like chromatin condensation and thus are functionally relevant for melanoma progression.
| S-EPMC9321645 | biostudies-literature
Project description:The nuclear lamina serves important roles in chromatin organization and structural support, and lamina mutations can result in laminopathies. Less is known about how nuclear lamina structure changes during cellular differentiation-changes that may influence gene regulation. We examined the structure and dynamics of the nuclear lamina in human-induced pluripotent stem cells (iPSCs) and differentiated germ layer cells, focusing on lamin B1. We report that lamin B1 dynamics generally increase as iPSCs differentiate, especially in mesoderm and ectoderm, and that lamin B receptor (LBR) partially redistributes from the nucleus to cytoplasm in mesoderm. Knocking down LBR in iPSCs led to an increase in lamin B1 dynamics, a change that was not observed for ELYS, emerin, or lamin B2 knockdown. LBR knockdown also affected expression of differentiation markers. These data suggest that differentiation-dependent tethering of lamin B1 either directly by LBR or indirectly via LBR-chromatin associations impacts gene expression.
| S-EPMC9930530 | biostudies-literature
Project description:The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1--but not lamin B2--is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.
| S-EPMC3666708 | biostudies-literature
Project description:Lamins (A/C and B) are major constituents of the nuclear lamina (NL). Structurally conserved lamina-associated domains (LADs) are formed by genomic regions that contact the NL. Lamins are also found in the nucleoplasm, with a yet unknown function. Here we map the genome-wide localization of lamin B1 in an euchromatin-enriched fraction of the mouse genome and follow its dynamics during the epithelial-to-mesenchymal transition (EMT). Lamin B1 associates with actively expressed and open euchromatin regions, forming dynamic euchromatin lamin B1-associated domains (eLADs) of about 0.3 Mb. Hi-C data link eLADs to the 3D organization of the mouse genome during EMT and correlate lamin B1 enrichment at topologically associating domain (TAD) borders with increased border strength. Having reduced levels of lamin B1 alters the EMT transcriptional signature and compromises the acquisition of mesenchymal traits. Thus, during EMT, the process of genome reorganization in mouse involves dynamic changes in eLADs.
| S-EPMC6109041 | biostudies-literature
Project description:The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to detachment of lamina-associated domains (LADs) from the nuclear periphery accompanied with global chromatin redistribution and decompaction. Consequently, the inter-chromosomal as well as inter-compartment interactions are increased, but the structure of topologically associating domains (TADs) is not affected. Using live-cell genomic loci tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, chromatin compaction, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting their crucial roles in chromatin higher-order structure and chromatin dynamics.
| S-EPMC8934373 | biostudies-literature