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. 2020 Mar 1:302:124-130.
doi: 10.1016/j.ijcard.2019.12.002. Epub 2019 Dec 6.

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

Charlotte L Hall  1 , Priyatansh Gurha  2 , Maria Sabater-Molina  3 , Angeliki Asimaki  4 , Marta Futema  1 , Ruth C Lovering  5 , Mari Paz Suárez  6 , Beatriz Aguilera  6 , Pilar Molina  7 , Esther Zorio  8 , Cristian Coarfa  9 , Matthew J Robertson  9 , Sirisha M Cheedipudi  2 , Keat-Eng Ng  10 , Paul Delaney  10 , Juan Pedro Hernández  11 , Francisco Pastor  12 , Juan R Gimeno  13 , William J McKenna  1 , Ali J Marian  2 , Petros Syrris  14
Affiliations

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

Charlotte L Hall et al. Int J Cardiol. .

Abstract

Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM. RNA was extracted from seven paraffin-embedded left ventricular tissue samples from deceased ACM patients carrying FLNC variants and sequenced. Transcript levels of 623 genes were upregulated and 486 genes were reduced in ACM in comparison to control samples. The cell adhesion pathway and ILK signalling were among the prominent dysregulated pathways in ACM. Consistent with these findings, transcript levels of cell adhesion genes JAM2, NEO1, VCAM1 and PTPRC were upregulated in ACM samples. Moreover, several actin-associated genes, including FLNC, VCL, PARVB and MYL7, were suppressed, suggesting dysregulation of the actin cytoskeleton. Analysis of the transcriptome for dysregulated biological pathways predicted activation of inflammation and apoptosis and suppression of oxidative phosphorylation and MTORC1 signalling in ACM. Our data suggests dysregulated cell adhesion and ILK signalling as novel putative pathogenic mechanisms of ACM caused by FLNC variants which are distinct from the postulated disease mechanism of classic ARVC caused by desmosomal gene mutations. This knowledge could help in the design of future gene therapy strategies which would target specific components of these pathways and potentially lead to novel treatments for ACM.

Keywords: Arrhythmogenic cardiomyopathy; Filamin C; Focal adhesion pathway; Integrin linked kinase pathway; RNA sequencing.

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Conflict of interest statement

Declaration of competing interest None.

Figures

Fig. 1.
Fig. 1.
Dysregulated gene expression in ACM cardiac tissue samples carrying FLNC variants. A). Volcano plots showing differentially expressed genes (q < 0.05) in ACM samples compared to controls. Z score plots showing transcriptional regulators targeting B). upregulated or C). downregulated genes. D). Gene set enrichment analysis plot of differentially expressed genes showing enrichment of genes involved in cell adhesion. E). Heatmap of dysregulated genes in the cell adhesion pathway.
Fig. 2.
Fig. 2.
Map displaying the most enriched GO terms for the FLNC variant carriers vs control group using WebGestalt [25]. The enriched GO terms are shown in the context of the ontology tree; the stronger the red colour in the GO term boxes, the more significant the enrichment is. The GO terms in the white boxes are not significantly enriched but are included in order to provide information about the parentage of the enriched terms. gNum, Number of genes in the gene set also in the category. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3.
Fig. 3.
Biological pathways disrupted in ACM cardiac tissue samples carrying FLNC variants identified by IPA analysis. A). Histogram of dysregulated canonical pathways. B). Heatmap of DEGs in the ILK pathway. C). Circos plot showing differentially expressed genes in the ILK signalling and inflammation pathways.
Fig. 4.
Fig. 4.
The ILK Signalling pathway generated using IPA. The genes with an outer pink border are present in this dataset. Those coloured in green are downregulated in the FLNC cardiac specimens and those that are coloured in red/pink are upregulated compared to the control group.
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