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: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.
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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 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:Lamin B1 is a component of the nuclear envelope involved in epigenetic chromatin regulation and is reduced during B cell activation and formation of lymphoid germinal centres. RNAi-mediated reduction of Lamin B1 results in spontaneous SHM as well as kappa-light chain aberrant surface expression showing that Lamin B1 is a negative epigenetic regulator of SHM. We used Affymetrix Exon 1.0 ST microarrays to detail the global programme of gene expression underlying changes induced in siRNA-treated Lamin B1low BL2 cells. siRNA-mediated reduction of nuclear Lamin B1 incorporation resulted in a general upregulation of positive cell cycle regulatory genes which in turn occurred alongside an upregulation of genes responsible for cell cycle checkpoint execution or cell cycle arrest, and were specific for LMNB1 reduction.
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Project description:Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We find major changes in chromatin compaction and localization of cardiac genes already in Lmna−/−ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate, accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal, and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. Importantly, we observe divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which has distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. Thus, disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy.
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Project description:The emergence of multidrug resistant tuberculosis and the increasing level of resistance urges the search for alternative drugs in treatment. Several neuroleptics, like thioridazine, reveal activity against Mycobacterium tuberculosis. Thioridazine was even successfully applied in compassionate therapy of extensively drug resistant tuberculosis in patients when added to other second and third line antibiotics. The synergistic effects between thioridazine and other anti-tuberculosis drugs is usually assigned to the inhibition of efflux pumps by thioridazine. Using an unbiased proteomic approach, we set out to unravel the molecular mechanism of this potential new anti-tuberculosis component by examining the impact of continuous thioridazine exposure on the proteome of M. tuberculosis. We discovered that under the influence of thioridazine several proteins involved in the maintenance of the cell wall permeability barrier are differentially regulated, while none of the known mycobacterial efflux pumps was differentially regulated on the protein level. By assessing accumulation of fluorescent dyes in M. tuberculosis over time, we demonstrated that long-term drug exposure of M. tuberculosis indeed affected the mycobacterial cell envelope and increased the permeability towards both hydrophilic and hydrophobic compounds. Furthermore, we demonstrated that treatment of M. tuberculosis with thioridazine altered the composition of the plasma membrane. Thioridazine induced an increase in cell envelope permeability, and thereby the enhanced uptake of compounds, this could explain the previously reported synergistic effects between thioridazine and other anti-tuberculosis drugs. Although the hypothesis of higher intercellular drug concentrations by THZ has not changed in this study, the more exact knowledge on its mode of action is a major step forward. This new insight in the molecular mechanism of this anti-tuberculosis compound could facilitate further development of this class of drugs for application in drug therapy of multidrug resistant tuberculosis. In fact, the efficacy of many existing drugs could be improved significantly.
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