Lamin B2 controls nuclear envelope permeability and regulates cardiomyocyte regeneration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA423262 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6397010_1.fastq.gz | Fastqsanger.gz | |||
| SRR6397010_2.fastq.gz | Fastqsanger.gz | |||
| SRR6397020_1.fastq.gz | Fastqsanger.gz | |||
| SRR6397020_2.fastq.gz | Fastqsanger.gz | |||
| SRR6397030_1.fastq.gz | Fastqsanger.gz |
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Project description:Heart muscle cells, cardiomyocytes, are highly differentiated cells that usually do not proliferate . During the non-proliferative state, extracellular signals control cardiomyocyte contractile function. However, during development and regeneration, cardiomyocytes enter the cell cycle and divide. It is unknown how cardiomyocytes modify their intracellular signaling to direct the cell cycle program. Here, we show that the nuclear lamina protein Lamin B2 (Lmnb2) regulates cardiomyocyte cell cycle activity using a gatekeeper mechanism. We identified Lmnb2 as a candidate for regulating intracellular signaling with deep transcriptional profiling of single cardiomyocytes. Lmnb2 was sufficient and necessary for cardiomyocyte cycling in the presence of serum. Lmnb2 increased the nucleoporin NUP98 and permeability of the nuclear membrane for phosphorylated ERK1/2. In vivo, the Lmnb2 gene was required for cardiomyocyte cell cycle activity during development. Increasing the expression of Lmnb2 in neonatal mice promoted cardiomyocyte M-phase and cytokinesis. LmnB2 gene transfer in neonatal mice that received a myocardial injury increased cardiomyocyte division and myocardial function in the injury border zone, indicating that the regenerated cardiomyocytes were functionally integrated. We propose a gatekeeper function of Lmnb2 that can be targeted to increase cardiomyocyte regeneration without the administration of exogenous growth factors.
2020-02-28 | GSE108360 | GEO
Project description:Small interfering RNA (siRNA) mediated depletion of Lamin A/C and Lamin B2 was performed in a diploid colorectal cancer cell line - DLD1 with an aim to identify transcription deregulation across the genome.
2016-09-24 | GSE73269 | GEO
Project description:Gene expression is regulated by chromatin DNA methylation and other features, including histone post-translational modifications (PTMs), chromatin remodelers, and transcription factor occupancy. A complete understanding of gene regulation will require the mapping of these chromatin features in small cell number samples. Here we describe a novel genome-wide chromatin profiling technology, named as Nicking Enzyme Epitope targeted DNA sequencing (NEED-seq). NEED-seq offers antibody-targeted controlled nicking by Nt.CviPII-pGL fusion to study specific protein-DNA complexes in formaldehyde fixed cells, allowing for both visual and genomic resolution of epitope bound chromatin. When applied to nuclei, NEED-seq yielded genome-wide profile of chromatin associated proteins and histone PTMs. Additionally, NEED-seq of lamin B1 and B2 demonstrated their association with heterochromatin. Lamin B1 and B2 associated domains (LAD) segregated to three different states, and states with stronger LAD correlated with heterochromatic marks. Hi-C analysis displayed A and B compartment with equal lamin B1 and B2 distribution, although methylated DNA remained high in B compartment. LAD clustering with Hi-C resulted in subcompartments, with lamin B1 and B2 partitioning to facultative and constitutive heterochromatin respectively and were associated with neuronal development. Thus, lamin B1 and B2 show structural and functional partitioning in mammalian nucleus.
2025-01-16 | GSE261834 | GEO
Project description:Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardiomyocytes of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.
2024-04-26 | GSE241577 | GEO
Project description:Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardiomyocytes of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.
2024-04-26 | GSE241589 | GEO
Project description:Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardiomyocytes of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.
2024-04-26 | GSE241587 | GEO
Project description:Heart regeneration requires cardiomyocyte proliferation. It is thought that formation of polyploid nuclei establishes a barrier for cardiomyocyte proliferation, but the mechanisms are largely unknown. Here, we show that the nuclear lamina filament Lamin B2 (Lmnb2), whose expression decreases in mice after birth, is essential for nuclear envelope breakdown prior to progression to metaphase and subsequent division. Inactivating Lmnb2 decreased metaphase progression, which led to formation of polyploid cardiomyocyte nuclei in neonatal mice, which, in turn, decreased myocardial regeneration. Increasing Lmnb2 expression promoted cardiomyocyte M-phase progression and cytokinesis and improved indicators of myocardial regeneration in neonatal mice. Inactivating LMNB2 in human iPS cell-derived cardiomyocytes reduced karyokinesis and increased formation of polyploid nuclei. In primary cardiomyocytes from human infants with heart disease, modifying LMNB2 expression correspondingly altered metaphase progression and ploidy of daughter nuclei. In conclusion, Lmnb2 expression is essential for karyokinesis in mammalian cardiomyocytes and heart regeneration.
| S-EPMC7346764 | biostudies-literature
Project description:The nuclear lamins are extremely long-lived proteins in most cell types. As a consequence, lamin function cannot be effectively dissected with temporal precision using standard knock-down approaches. Here, we apply the auxin inducible degron (AID) system to rapidly deplete each lamin isoform within one cell cycle and reveal the immediate impacts of lamin loss on the nucleus . Surprisingly, neither acute lamin A/C (LA/C), lamin B1 (LB1), nor lamin B2 (LB2) depletion altered nuclear shape or induced nuclear blebbing, indicating that acute lamin loss is not sufficient to alter nuclear morphology. LB1 depletion is immediately followed by LA/C meshwork disorganization due to actin cytoskeletal forces on the lamina, yet neither LA/C nor LB1 depletion induced nuclear rupturing. We found that the abundant inner nuclear membrane protein LAP2β protects nuclear integrity in the absence of LB1, as depletion of both LB1 and LAP2β induced severe LA/C disorganization and frequent nuclear rupturing. Depolymerization of the actin cytoskeleton halts nuclear rupture in LAP2β- and LB1-depleted nuclei. We conclude that both LB1 and LAP2β resist cytoskeletal force to maintain regular lamin A/C meshwork organization and preserve nuclear integrity.
2025-02-17 | GSE289252 | GEO
Project description:The nuclear lamina (NL) is a filamentous layer lining the inner-nuclear-membrane (INM) that aids in the organization of the genome in large domains of low transcriptional activity. Recently, it was shown that the single-cell genome-NL interactions are much more dynamic than previously anticipated, which challenges the concept of the NL as a safe guard for transcriptional repressed genes. Here we discuss the role of the NL in light of these new findings and introduce Lamin A and BAF as potential modulators of LAD positioning BAF-chromatin and Lamin B2-chromatin interactions were assayed in human HT1080 by DamID on Nimblegen microarrays, with two biological replicates each, that were hybridized in a dye-swap design.
2014-02-15 | E-GEOD-55066 | biostudies-arrayexpress
Project description:The integrity of the nuclear envelope (NE) is essential to maintain the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events have also been described, without any obvious physical challenges to the cell. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation can lead to NE rupture. Upon DNA damage, Lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA damage-based chemotherapy.
2023-10-09 | PXD040857 | Pride