RNA sequencing-based transcriptome profiling of cardiac tissue implicates novel putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy

Hall, Charlotte; Gurha, Priyatansh; Sabater-Molina, María; Asimaki, Angeliki; Futema, Marta; Lovering, Ruth C.; Suárez, Mari Paz; Aguilera, Beatriz; Molina, Pilar; Zorio, Esther; Coarfa, Cristian; Robertson, Matthew J.; Cheedipudi, Sirisha; Ng, Keat‐Eng; Delaney, Paul J.; Hernández, Juan Pedro Rodríguez; Pastor, Francisco; Gimeno, Juan R.; McKenna, William J.; Marian, Ali J.; Syrris, Petros

doi:10.1016/j.ijcard.2019.12.002

Cited by 26 publications

(22 citation statements)

References 25 publications

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“…This could contribute to loosening of cell contacts and death of cardiomyocytes [ 52 ]. In addition, rare mutations in genes involved in the coupling of the cardiomyocytes to the ECM like FLNC or ILK have been recently described in ARVC families [ 53 , 54 ]. As desmosomes are additionally important to maintain the coordination of cardiomyocytes [ 55 ], an affected ECM and therefore lower affinity of desmosomal cadherins might contribute to ventricular arrhythmia.…”

Section: Discussionmentioning

confidence: 99%

Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes

Sielemann

Elbeck

Gärtner

et al. 2020

Genes

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Cardiovascular diseases are the number one cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well understood. Cardiomyopathies are primary diseases of the heart muscle and contribute to high rates of heart failure and sudden cardiac deaths. Here, we distinguished four different genetic cardiomyopathies based on gene expression signatures. In this study, RNA-Sequencing was used to identify gene expression signatures in myocardial tissue of cardiomyopathy patients in comparison to non-failing human hearts. Therefore, expression differences between patients with specific affected genes, namely LMNA (lamin A/C), RBM20 (RNA binding motif protein 20), TTN (titin) and PKP2 (plakophilin 2) were investigated. We identified genotype-specific differences in regulated pathways, Gene Ontology (GO) terms as well as gene groups like secreted or regulatory proteins and potential candidate drug targets revealing specific molecular pathomechanisms for the four subtypes of genetic cardiomyopathies. Some regulated pathways are common between patients with mutations in RBM20 and TTN as the splice factor RBM20 targets amongst other genes TTN, leading to a similar response on pathway level, even though many differentially expressed genes (DEGs) still differ between both sample types. The myocardium of patients with mutations in LMNA is widely associated with upregulated genes/pathways involved in immune response, whereas mutations in PKP2 lead to a downregulation of genes of the extracellular matrix. Our results contribute to further understanding of the underlying molecular pathomechanisms aiming for novel and better treatment of genetic cardiomyopathies.

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Section: Discussionmentioning

confidence: 99%

Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes

Sielemann

Elbeck

Gärtner

et al. 2020

Genes

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“…Loss of FLNC in mouse myocardium lead to upregulation of several adhesion proteins including b1D-integrin, Talin1, Kindlin2, Focal Adhesion Kinase, Vinculin and Integrin-Linked Kinase (ILK) [ 29 ]. Similarly, RNA-sequencing of cardiac samples of ARVC patients with FLNC loss of function variants revealed differential expression of genes, involved in cell adhesion, especially highlighting the importance of ILK signaling [ 30 ]. This link between structural sarcomeric gene mutations and cell adhesion proteins was also suggested in our previous study using a bioinformatic approach [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

FLNC Expression Level Influences the Activity of TEAD-YAP/TAZ Signaling

Knyazeva

Khudiakov

Vaz

et al. 2020

Genes

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Filamin C (FLNC), being one of the major actin-binding proteins, is involved in the maintenance of key muscle cell functions. Inherited skeletal muscle and cardiac disorders linked to genetic variants in FLNC have attracted attention because of their high clinical importance and possibility of genotype-phenotype correlations. To further expand on the role of FLNC in muscle cells, we focused on detailed alterations of muscle cell properties developed after the loss of FLNC. Using the CRISPR/Cas9 method we generated a C2C12 murine myoblast cell line with stably suppressed Flnc expression. FLNC-deficient myoblasts have a significantly higher proliferation rate combined with an impaired cell migration capacity. The suppression of Flnc expression leads to inability to complete myogenic differentiation, diminished expression of Myh1 and Myh4, alteration of transcriptional dynamics of myogenic factors, such as Mymk and Myog, and deregulation of Hippo signaling pathway. Specifically, we identified elevated basal levels of Hippo activity in myoblasts with loss of FLNC, and ineffective reduction of Hippo signaling activity during myogenic differentiation. The latter was restored by Flnc overexpression. In summary, we confirmed the role of FLNC in muscle cell proliferation, migration and differentiation, and demonstrated for the first time the direct link between Flnc expression and activity of TEAD-YAP\TAZ signaling. These findings support a role of FLNC in regulation of essential muscle processes relying on mechanical as well as signaling mechanisms.

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“…Moreover, Flnc, Lgals3, and Prkaca showed strong presence at the single cell level. Flnc is involved in actin cytoskeleton organization in heart and skeletal muscle, and previous studies have shown that this gene has critical role in CVD (Hall et al, 2020;Zhou et al, 2020). Similarly, Prkaca, an important metabolic gene, has also been shown to play an important function during CVD (Bers, 2008;Diviani et al, 2011;Turnham and Scott, 2016).…”

Section: Discussionmentioning

confidence: 98%

Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction

Arif

Klevstig

Benfeitas

et al. 2020

Preprint

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Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genome-wide transcriptomic analysis on tissue samples obtained 6- and 24-hours post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI; and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in independent MI cohorts, using both bulk and single-cell transcriptomic data. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.

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RNA sequencing-based transcriptome profiling of cardiac tissue implicates novel putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy

Cited by 26 publications

References 25 publications

Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes

Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes

FLNC Expression Level Influences the Activity of TEAD-YAP/TAZ Signaling

Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction

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