Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy

ABSTRACT: Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy

PROVIDER: PRJNA799748 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR17712156.fastq.gz	Fastqsanger.gz
	SRR17712157.fastq.gz	Fastqsanger.gz
	SRR17712158.fastq.gz	Fastqsanger.gz
	SRR17712159.fastq.gz	Fastqsanger.gz
	SRR17712160.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 12

Similar Datasets

Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy

Project description:Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, which primarily affect the heart and skeletal muscle. A mutation in the NEP LEMD2 causes severe cardiomyopathy in humans. However, the roles of LEMD2 in the heart and the pathological mechanisms responsible for its association with cardiac disease are unknown. To explore the mechanistic basis of this pathology, we generated mice carrying the human c.T38>G LEMD2 mutation. These mice phenocopied the human disease and developed severe dilated cardiomyopathy with extensive cardiac fibrosis leading to premature death. At the cellular level, LEMD2 mutant cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. Moreover, mice with cardiac-specific deletion of LEMD2 also died shortly after birth due to heart abnormalities. LEMD2 mutant mice displayed aberrant cardiac gene expression and extensive DNA damage. The development of cardiac disease in both mouse models is linked to p53 activation. Together, our results reveal the essentiality of the nuclear envelope protein LEMD2 for genome stability and normal cardiac function.

2022-10-13 | GSE194218 | GEO

Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice [mRNA-seq]

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

Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin cardiomyopathy mice [SLAM-IT-seq]

2024-04-26 | GSE241589 | GEO

Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin cardiomyopathy mice [sci-RNA-seq]

2024-04-26 | GSE241587 | GEO

Lem2 is essential for cardiac development by maintaining nuclear integrity

Project description:Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.

2023-09-13 | GSE217693 | GEO

Loss of function of the nuclear envelope protein LEMD2 causes DNA damage-dependent cardiomyopathy.

Project description:Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, that primarily affect the heart and skeletal muscle. A mutation in the NEP LEM domain-containing protein 2 (LEMD2) causes severe cardiomyopathy in humans. However, the roles of LEMD2 in the heart and the pathological mechanisms responsible for its association with cardiac disease are unknown. We generated knockin (KI) mice carrying the human c.T38>G Lemd2 mutation, which causes a missense amino acid exchange (p.L13>R) in the LEM domain of the protein. These mice represent a preclinical model that phenocopies the human disease, as they developed severe dilated cardiomyopathy and cardiac fibrosis leading to premature death. At the cellular level, KI/KI cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. Moreover, mice with cardiac-specific deletion of Lemd2 also died shortly after birth due to heart abnormalities. Cardiomyocytes lacking Lemd2 displayed nuclear envelope deformations and extensive DNA damage and apoptosis linked to p53 activation. Importantly, cardiomyocyte-specific Lemd2 gene therapy via adeno-associated virus rescued cardiac function in KI/KI mice. Together, our results reveal the essentiality of LEMD2 for genome stability and cardiac function and unveil its mechanistic association with human disease.

| S-EPMC9663152 | biostudies-literature

The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization

Project description:Lamins and transmembrane proteins within the nuclear envelope regulate nuclear structure and chromatin organization. Nuclear Envelope Transmembrane Protein 39 (Net39) is muscle nuclear envelope protein whose functions in vivo have not been explored. We show that mice lacking Net39 succumb to severe myopathy and juvenile lethality, with concomitant disruption in nuclear integrity, chromatin accessibility, gene expression and metabolism. These abnormalities resemble those of Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in A-type Lamins (LMNA) and other genes, like Emerin (EMD). We observe that Net39 is downregulated in EDMD patients, implicating Net39 in the pathogenesis of this disorder. Our findings highlight the role of Net39 at the nuclear envelope in maintaining muscle chromatin organization, gene expression and function, and its potential contribution to the molecular etiology of EDMD.

2020-11-23 | GSE154850 | GEO

DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of Lamin A/C

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

Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice

Project description:Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice

| PRJNA1008739 | ENA

The nuclear envelope protein Net39 is essential for nuclear integrity, chromatin organization, and muscle growth (RNA-Seq)

Project description:Lamins and transmembrane proteins within the nuclear envelope are regulators of nuclear structure and chromatin organization. Nuclear Envelope Transmembrane Protein 39 (Net39) is a muscle-restricted nuclear envelope protein. We show that mice lacking Net39 succumb to severe myopathy and neonatal lethality, with concomitant disruption in nuclear integrity, chromatin accessibility, gene expression and metabolism. These abnormalities resemble those of Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in A-type Lamins (LMNA) and other genes, like Emerin (EMD). We observe that Net39 is downregulated in EDMD patients, implicating Net39 in the pathogenesis of this disorder. Our findings reveal an intimate role for the nuclear envelope in maintaining muscle chromatin organization, gene expression and function, and highlight the importance of Net39 in these processes and in the molecular etiology of EDMD.

2020-11-24 | GSE154849 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data