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

Caravia, Xurde M.; Ramirez-Martinez, Andres; Gan, Peiheng; Wang, Rui; McAnally, John; Xu, Lin; Bassel‐Duby, Rhonda; Liu, Ning; Olson, Eric N.

doi:10.1172/jci158897

Cited by 10 publications

(9 citation statements)

References 58 publications

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“…Thus, from our results, NLI is associated with the long-term DNA instability, telomere injure, and features of stemness. All these features were previously associated with cardiac diseases and failure [ 74 , 75 ].…”

Section: Resultsmentioning

confidence: 99%

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

Anatskaya

Runov

Ponomartsev

et al. 2023

IJMS

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Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic effects on cardiac developmental programs and cardiomyocyte transcriptome regulation. Using the rat model of NLI triggered by lactase overloading with lactose and the methods of cytophotometry, image analysis, and mRNA-seq, we evaluated cardiomyocyte ploidy, signs of DNA damage, and NLI-associated long-term transcriptomic changes of genes and gene modules that differed qualitatively (i.e., were switched on or switched off) in the experiment vs. the control. Our data indicated that NLI triggers the long-term animal growth retardation, cardiomyocyte hyperpolyploidy, and extensive transcriptomic rearrangements. Many of these rearrangements are known as manifestations of heart pathologies, including DNA and telomere instability, inflammation, fibrosis, and reactivation of fetal gene program. Moreover, bioinformatic analysis identified possible causes of these pathologic traits, including the impaired signaling via thyroid hormone, calcium, and glutathione. We also found transcriptomic manifestations of increased cardiomyocyte polyploidy, such as the induction of gene modules related to open chromatin, e.g., “negative regulation of chromosome organization”, “transcription” and “ribosome biogenesis”. These findings suggest that ploidy-related epigenetic alterations acquired in the neonatal period permanently rewire gene regulatory networks and alter cardiomyocyte transcriptome. Here we provided first evidence indicating that NLI can be an important trigger of developmental programming of adult cardiovascular disease. The obtained results can help to develop preventive strategies for reducing the NLI-associated adverse effects of inflammation on the developing cardiovascular system.

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Section: Resultsmentioning

confidence: 99%

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

Anatskaya

Runov

Ponomartsev

et al. 2023

IJMS

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“…These cells displayed a reduction in the NE-associated LEMD2 protein in CS-A cells, resulting in decreased formation of lamin A/C-LEMD2 complexes at the NE. LEMD2 has a well-established role in the maintenance of NE morphology and cell survival (40,54). Our findings are consistent with a previous study showing that LEMD2 depletion leads to NE defects without affecting the localization or expression of lamin A/C and lamin B1 (40).…”

Section: Discussionmentioning

confidence: 99%

A Novel Role for CSA in the Regulation of Nuclear Envelope Integrity: Uncovering a Non-Canonical Function

Yang,

Lai,

Davies

et al. 2023

Preprint

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Cockayne syndrome (CS) is an autosomal recessive premature ageing condition mainly characterized by microcephaly, growth failure, and neurodegeneration. It is caused by mutations inERCC6orERCC8genes which encode for Cockayne Syndrome B (CSB) and Cockayne Syndrome A (CSA) proteins, respectively. CSA and CSB have well-characterised roles in transcription-coupled nucleotide excision repair (TC-NER), responsible for the removal of bulky DNA lesions, including those caused by UV irradiation. Here, we report that CSA knockout cells and CSA patient cells (CS-A) carrying a loss-of-function mutation in theERCC8gene exhibit defects in nuclear envelope (NE) integrity. NE dysfunction is a characteristic phenotype of cells from progeroid disorders caused by mutation in NE proteins, such as Hutchinson-Gilford Progeria Syndrome (HGPS). However, it has never been reported in Cockayne Syndrome. We observed that CS-A cells displayed reduced levels of LAP2-emerin-MAN1 (LEM)-domain 2 (LEMD2) at the NE resulting in decreased formation of LEMD2-lamin A/C complexes. In addition, loss of CSA function caused increased actin stress fibers that contributed to enhanced mechanical stress to the NE. Altogether, these led to NE blebbing and ruptures in interphase, causing activation of the innate/immune cGAS/STING signaling pathway. Disrupting the linker of the nucleoskeleton and cytoskeleton (LINC) complex that is responsible for anchoring the cytoskeleton to the NE, rescued the NE phenotypes and reduced the activation of cGAS/STING pathway. This work has revealed a previously uncharacterized role for CSA in regulating NE integrity and shed light on mechanisms that may further explain some of the clinical phenotypes observed in CS patients such as neuroinflammation. This is to our knowledge, the first study showing NE dysfunction in a progeroid syndrome caused by mutations in a DNA damage repair protein, reinforcing the connection between NE deregulation and ageing.

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“…Homozygous desmin knockout and knockin mice display the typical cardiac involvement (LV thinning, fibrosis, and systolic dysfunction) of autosomal-recessive desminopathies [ 155 ]. Progressive DCM sustained by cardiomyocyte nuclear envelope disarrangement (envelopathy) can be produced by a knockin mutation of the LEDM2 gene in mice [ 156 ]. Manipulating the expression of desmosomal genes (especially desmocollin-2 and desmoglein-2) causes the development of severe biventricular cardiomyopathy in mice, triggered by an acute inflammatory process leading to cardiomyocyte necrosis and fibrosis [ 157 ].…”

Section: Genetic Modelsmentioning

confidence: 99%

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

Ponzoni

Coles

Maynes

2023

IJMS

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Even with modern therapy, patients with heart failure only have a 50% five-year survival rate. To improve the development of new therapeutic strategies, preclinical models of disease are needed to properly emulate the human condition. Determining the most appropriate model represents the first key step for reliable and translatable experimental research. Rodent models of heart failure provide a strategic compromise between human in vivo similarity and the ability to perform a larger number of experiments and explore many therapeutic candidates. We herein review the currently available rodent models of heart failure, summarizing their physiopathological basis, the timeline of the development of ventricular failure, and their specific clinical features. In order to facilitate the future planning of investigations in the field of heart failure, a detailed overview of the advantages and possible drawbacks of each model is provided.

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

Cited by 10 publications

References 58 publications

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

A Novel Role for CSA in the Regulation of Nuclear Envelope Integrity: Uncovering a Non-Canonical Function

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

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