Splicing factors in the heart: Uncovering shared and unique targets

Montañés-Agudo, Pablo; Pinto, Yigal M.; Creemers, Esther E.

doi:10.1016/j.yjmcc.2023.04.003

Cited by 12 publications

(8 citation statements)

References 44 publications

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“…It is of note that cardiomyopathy-associated RBPs display both redundant and specific regulatory functions in cardiac alternative splicing, which is important for the expression and switching of cardiac-specific protein isoforms. Therefore, the interplay between different RBPs coordinates the alternative splicing events of common and specific target genes, whereas variation in the expression levels of individual RBPs may cause aberrant splicing and may contribute to cardiac disease [ 99 ]. It has been shown that Rbm20 and Rbm24 physically interact to regulate alternative splicing of the Enigma homolog ( Enh ) gene, also known as Pdlim5 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we may expect that their combined actions coordinate alternative splicing events in heart development, function, and homeostasis. Indeed, it is suggested that, similar to the loss of Rbm24, aberrant splicing due to the dysregulated expression of MBNL and QKI could contribute to the disease mechanism underlying the pathogenesis of heart failure [ 99 ]. Since many RBPs are dysregulated in cardiac hypertrophy or heart failure, modulating their expression or activity may represent a potential to rescue cardiovascular dysfunction [ 103 ].…”

Section: Discussionmentioning

confidence: 99%

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RNA-Binding Proteins in Cardiomyopathies

Shi

2024

JCDD

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The post-transcriptional regulation of gene expression plays an important role in heart development and disease. Cardiac-specific alternative splicing, mediated by RNA-binding proteins, orchestrates the isoform switching of proteins that are essential for cardiomyocyte organization and contraction. Dysfunctions of RNA-binding proteins impair heart development and cause the main types of cardiomyopathies, which represent a heterogenous group of abnormalities that severely affect heart structure and function. In particular, mutations of RBM20 and RBFOX2 are associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or hypoplastic left heart syndrome. Functional analyses in different animal models also suggest possible roles for other RNA-binding proteins in cardiomyopathies because of their involvement in organizing cardiac gene programming. Recent studies have provided significant insights into the causal relationship between RNA-binding proteins and cardiovascular diseases. They also show the potential of correcting pathogenic mutations in RNA-binding proteins to rescue cardiomyopathy or promote cardiac regeneration. Therefore, RNA-binding proteins have emerged as promising targets for therapeutic interventions for cardiovascular dysfunction. The challenge remains to decipher how they coordinately regulate the temporal and spatial expression of target genes to ensure heart function and homeostasis. This review discusses recent advances in understanding the implications of several well-characterized RNA-binding proteins in cardiomyopathies, with the aim of identifying research gaps to promote further investigation in this field.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RNA-Binding Proteins in Cardiomyopathies

Shi

2024

JCDD

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“…Our enrichment analysis for the RV vs LV comparison revealed two biological processes, which were associated with alternative RNA splicing: cardiac muscle contraction (GO:0060048) (FDR=0.00767). One of the most striking observations was the differential expression of transcript isoforms of the Tropomyosin 2-beta (Tpm2) gene, another known regulator of muscle contraction (Figure 5) which is shown to be commonly spliced in the heart (36).…”

Section: Alternative Usage Of Tpm2 Variants Between Rv and LVmentioning

confidence: 99%

Transverse Aortic COnstriction Multi-omics Analysis (TACOMA) uncovers pathophysiological cardiac molecular mechanisms

Gjerga,

Dewenter,

Britto-Borges

et al. 2024

Preprint

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Time-course multi-omics data of a murine model of progressive heart failure induced by transverse aortic constriction (TAC) provide insights into the molecular mechanisms that are causatively involved in contractile failure and structural cardiac remodelling. We employ Illumina-based transcriptomics, Nanopore sequencing, and mass spectrometry-based proteomics on samples from the left ventricle (LV) and right ventricle (RV, RNA only) of the heart at 1, 7, 21, and 56 days following TAC and Sham surgery. Here, we present TACOMA, as an interactive web-application that integrates and visualizes transcriptomics and proteomics data collected in a TAC time-course experiment. TACOMA enables users to visualize the expression profile of known and novel genes and protein products thereof. Importantly, we capture alternative splicing events by assessing differential transcript and exon usage as well. Co-expression-based clustering algorithms and functional enrichment analysis revealed overrepresented annotations of biological processes and molecular functions at the protein and gene levels. To enhance data integration, TACOMA synchronizes transcriptomics and proteomics profiles, enabling cross-omics comparisons. With TACOMA (https://shiny.dieterichlab.org/app/tacoma), we offer a rich web-based resource to uncover molecular events and biological processes implicated in contractile failure and cardiac hypertrophy. For example, we highlight: (i) changes in metabolic genes and proteins in the time course of hypertrophic growth and contractile impairment; (ii) identification of RNA splicing changes in the expression of Tpm2 isoforms between RV and LV; and (iii) novel transcripts and genes likely contributing to the pathogenesis of heart failure. We plan to extend these data with additional environmental and genetic models of heart failure to decipher common and distinct molecular changes in heart diseases of different aetiologies.

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“… 114 In addition, MBNL, RBM24 and QKI have multiple overlapping AS targets in the heart, including Sorbs2 , Mef2d , Lmo7 and Mff . 115 The ability to accurately predict complex AS patterns under the condition that multiple AS regulators are involved would greatly advance the field.…”

Section: Outstanding Questions and Future Directionsmentioning

confidence: 99%

Therapeutic potential of alternative splicing in cardiovascular diseases

Cao,

Wei,

Nie

et al. 2024

eBioMedicine

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Splicing factors in the heart: Uncovering shared and unique targets

Cited by 12 publications

References 44 publications

RNA-Binding Proteins in Cardiomyopathies

RNA-Binding Proteins in Cardiomyopathies

Transverse Aortic COnstriction Multi-omics Analysis (TACOMA) uncovers pathophysiological cardiac molecular mechanisms

Therapeutic potential of alternative splicing in cardiovascular diseases

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