Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency

Diofano, Federica; Weinmann, Karolina; Schneider, Isabelle; Thiessen, Kevin; Rottbauer, Wolfgang; Just, Steffen

doi:10.1371/journal.pgen.1009088

Cited by 18 publications

(27 citation statements)

References 44 publications

(96 reference statements)

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“…For example, BAG3 belongs to the BAG protein family acting as a chaperone molecular via physical interaction with Hsp70, HSPBs. It was shown that mutated BAG3 caused DCM, leading to systolic dysfunction, HF, and myofibrillar myopathy ( Sturner and Behl, 2017 ; Diofano et al, 2020 ). BAG2 was also a member of the human BAG protein family and is expressed in brown adipose, lung, heart, and other tissues.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Shi

Cao

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Background: Myocardial infarction (MI) is one of the leading threats to human health. N6-methyladenosine (m6A) modification, as a pivotal regulator of messenger RNA stability, protein expression, and cellular processes, exhibits important roles in the development of cardiac remodeling and cardiomyocyte contractile function.Methods: The expression levels of m6A regulators were analyzed using the GSE5406 database. We analyzed genome-wide association study data and single-cell sequencing data to confirm the functional importance of m6A regulators in MI. Three molecular subtypes with different clinical characteristics were established to tailor treatment strategies for patients with MI. We applied pathway analysis and differentially expressed gene (DEG) analysis to study the changes in gene expression and identified four common DEGs. Furthermore, we constructed the protein–protein interaction network and confirmed several hub genes in three clusters of MI. To lucubrate the potential functions, we performed a ClueGO analysis of these hub networks.Results: In this study, we identified that the levels of FTO, YTHDF3, ZC3H13, and WTAP were dramatically differently expressed in MI tissues compared with controls. Bioinformatics analysis showed that DEGs in MI were significantly related to modulating calcium signaling and chemokine signaling, and m6A regulators were related to regulating glucose measurement and elevated blood glucose levels. Furthermore, genome-wide association study data analysis showed that WTAP single-nucleotide polymorphism was significantly related to the progression of MI. In addition, single-cell sequencing found that WTAP is widely expressed in the heart tissues. Moreover, we conducted consensus clustering for MI in view of the dysregulated m6A regulators’ expression in MI. According to the expression levels, we found MI patients could be clustered into three subtypes. Pathway analysis showed the DEGs among different clusters in MI were assigned to HIF-1, IL-17, MAPK, PI3K-Akt signaling pathways, etc. The module analysis detected several genes, including BAG2, BAG3, MMP2, etc. We also found that MI-related network was significantly related to positive and negative regulation of angiogenesis and response to heat. The hub networks in MI clusters were significantly related to antigen processing and ubiquitin-mediated proteolysis, RNA splicing, and stability, indicating that these processes may contribute to the development of MI.Conclusion: Collectively, our study could provide more information for understanding the roles of m6A in MI, which may provide a novel insight into identifying biomarkers for MI treatment and diagnosis.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Shi

Cao

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…Inhibition of mTOR signaling improves cardiac function and hence, could be a target gene for therapeutic treatment of DCM caused by mutations in Bag3 ( Ding et al, 2019 ). However, CRISPR-Cas9 generated knockout of bag3 fails to show a DCM phenotype in adult zebrafish due to compensation by bag2 ( Diofano et al, 2020 ). These studies also demonstrate how genetic compensation may influence the penetrance of disease-causing mutations in vivo , and underscores the importance of comparing various gene-editing techniques and solving possible discrepancies.…”

Section: Genetic Heart Failure Modelsmentioning

confidence: 99%

Zebrafish Heart Failure Models

Narumanchi

Wang

Perttunen

et al. 2021

Front. Cell Dev. Biol.

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Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete. Zebrafish has proven useful for modeling human heart diseases due to similarity of zebrafish and mammalian hearts, fast easily tractable development, and readily available genetic methods. Embryonic cardiac development is rapid and cardiac function is easy to observe and quantify. Reverse genetics, by using morpholinos and CRISPR-Cas9 to modulate gene function, make zebrafish a primary animal model for in vivo studies of candidate genes. Zebrafish are able to effectively regenerate their hearts following injury. However, less attention has been given to using zebrafish models to increase understanding of heart failure and cardiac remodeling, including cardiac hypertrophy and hyperplasia. Here we discuss using zebrafish to study heart failure and cardiac remodeling, and review zebrafish genetic, drug-induced and other heart failure models, discussing the advantages and weaknesses of using zebrafish to model human heart disease. Using zebrafish models will lead to insights on the pathomechanisms of heart failure, with the aim to ultimately provide novel therapies for the prevention and treatment of heart failure.

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“…Diofano et al investigated the consequences of CRISPR/Cas9-induced zebrafish knockout of co-chaperone Bcl2-associated athanogene 3 ( bag3 ) wherein the bag3 morphant has been documented to cause cardiovascular defects including dilated cardiomyopathy and myofibrillar myopathy [ 37 ]. The authors found that the bag3 homozygous mutant had a surprisingly complete and preserved skeletal muscle structure and heart formation despite confirmation of substantially reduced bag3 mRNA levels.…”

Section: Gene Compensation Examplesmentioning

confidence: 99%

“…The injection of bag2 splice-blocking morpholino into bag3 mutant embryos recapitulated the cardiovascular defects witnessed in the bag3 morphant. Diofano et al further demonstrated that the inhibition of the nonsense-mediated mRNA decay pathway via NMD essential gene upf1 knockdown in bag3 mutants prevented the degradation of mutant bag3 mRNA, foiling compensation by bag2 and leading to the expected heart and skeletal muscle defects [ 37 ].…”

Section: Gene Compensation Examplesmentioning

confidence: 99%

Genotype to Phenotype: CRISPR Gene Editing Reveals Genetic Compensation as a Mechanism for Phenotypic Disjunction of Morphants and Mutants

Salanga

2021

IJMS

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Forward genetic screens have shown the consequences of deleterious mutations; however, they are best suited for model organisms with fast reproductive rates and large broods. Furthermore, investigators must faithfully identify changes in phenotype, even if subtle, to realize the full benefit of the screen. Reverse genetic approaches also probe genotype to phenotype relationships, except that the genetic targets are predefined. Until recently, reverse genetic approaches relied on non-genomic gene silencing or the relatively inefficient, homology-dependent gene targeting for loss-of-function generation. Fortunately, the flexibility and simplicity of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system has revolutionized reverse genetics, allowing for the precise mutagenesis of virtually any gene in any organism at will. The successful integration of insertions/deletions (INDELs) and nonsense mutations that would, at face value, produce the expected loss-of-function phenotype, have been shown to have little to no effect, even if other methods of gene silencing demonstrate robust loss-of-function consequences. The disjunction between outcomes has raised important questions about our understanding of genotype to phenotype and highlights the capacity for compensation in the central dogma. This review describes recent studies in which genomic compensation appears to be at play, discusses the possible compensation mechanisms, and considers elements important for robust gene loss-of-function studies.

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Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency

Cited by 18 publications

References 44 publications

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Zebrafish Heart Failure Models

Genotype to Phenotype: CRISPR Gene Editing Reveals Genetic Compensation as a Mechanism for Phenotypic Disjunction of Morphants and Mutants

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