The Emerging Role of the RBM20 and PTBP1 Ribonucleoproteins in Heart Development and Cardiovascular Diseases

Fochi, Stefania; Lorenzi, Pamela; Galasso, Marilisa; Stefani, Chiara; Trabetti, Elisabetta; Zipeto, Donato

doi:10.3390/genes11040402

Cited by 29 publications

(29 citation statements)

References 158 publications

(209 reference statements)

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“…Caruso et al observed the downregulation of miR-124 in patients with pulmonary arterial hypertension and its central role in contributing to abnormal cell proliferation via PTBP1 and PKM2 [26]. Recently, Fochi et al showed the emerging role of RBM20 and PTBP1 as key splicing factors in heart development and cardiovascular disease [27].…”

Section: Discussionmentioning

confidence: 99%

Identification of biological correlates associated with respiratory failure in COVID-19

Tannenbaum

Deasy

2020

BMC Med Genomics

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Background Coronavirus disease 2019 (COVID-19) is a global public health concern. Recently, a genome-wide association study (GWAS) was performed with participants recruited from Italy and Spain by an international consortium group. Methods Summary GWAS statistics for 1610 patients with COVID-19 respiratory failure and 2205 controls were downloaded. In the current study, we analyzed the summary statistics with the information of loci and p-values for 8,582,968 single-nucleotide polymorphisms (SNPs), using gene ontology analysis to determine the top biological processes implicated in respiratory failure in COVID-19 patients. Results We considered the top 708 SNPs, using a p-value cutoff of 5 × 10− 5, which were mapped to the nearest genes, leading to 144 unique genes. The list of genes was input into a curated database to conduct gene ontology and protein-protein interaction (PPI) analyses. The top ranked biological processes were wound healing, epithelial structure maintenance, muscle system processes, and cardiac-relevant biological processes with a false discovery rate < 0.05. In the PPI analysis, the largest connected network consisted of 8 genes. Through a literature search, 7 out of the 8 gene products were found to be implicated in both pulmonary and cardiac diseases. Conclusion Gene ontology and PPI analyses identified cardio-pulmonary processes that may partially explain the risk of respiratory failure in COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Identification of biological correlates associated with respiratory failure in COVID-19

Tannenbaum

Deasy

2020

BMC Med Genomics

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“…Whereas PTBP1 is required for the differentiation of iPSCs and fibroblasts to cardiomyocytes in vitro (49), and modulates the splicing of essential genes for cardiomyocyte function (e.g. Titin, Tropomyosin 1 and 2 and Mef2) (19), its role in the heart was virtually unknown. PTBP1 expression decreased during embryonic development and postnatally and was upregulated after MI or TAC.…”

Section: Discussionmentioning

confidence: 99%

“…Even considering a single RBP alone, several molecules may be required to bind stably to the target RNA, as shown specifically for PTBP1 (8), such that binding specificity is achieved by cooperative binding on nearby low affinity binding sites. Not only PTBP1 molecules bind cooperatively among themselves, but they can interact with MBNL1 proteins and cooperatively bind and modulate the inclusion of Tropomyosin exon 3 (28) or with RBM20 to regulate Titin AS (19). If interactions are widespread, a simple additive model with independent effects for all RBPs may fail to identify the actual regulatory elements, since their effects will be highly dependent on the factors that simultaneously bind each target.…”

Section: Discussionmentioning

confidence: 99%

PTBP1 promotes cardiac hypertrophy and diastolic dysfunction by modulating alternative splicing

Martí-Gómez

Larrasa-Alonso

López-Olañeta

et al. 2020

Preprint

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Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants and individual RNA binding proteins (RBPs); however, the global regulation of AS in cardiac pathophysiology and its interaction with gene expression (GE) is poorly understood. In this study we aimed to identify the AS profiles that characterize heart disease and their relationship with heart development, and to investigate the regulatory mechanisms controlling AS dynamics in the mouse heart. We studied the AS profiles in several developmental stages and diseases using a total of 144 RNA-seq samples. We found that AS and GE changes affect genes involved in distinct biological functions and have different impact on protein-protein interaction networks. In contrast to cancer, most changes in AS in the heart tended to maintain protein interaction patterns. AS changes showed a stronger functional impact in heart development compared to adult cardiac diseases, and were mainly regulated by MBNL1. Regulatory patterns in cardiac disease were more complex, characterized by more interactions between regulatory proteins. We found PTBP1 as potential mediator of the partial re-expression of neonatal AS patterns in cardiac diseases. PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction in adult mice.

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“…Further study on the consequences of Rbm24 deficiency in post-natal heart development using conditional knockout mice indicates a global disruption of alternative splicing events, which mostly affects those genes coding for sarcomere structure proteins involved in muscle contraction, including in particular Ttn [ 19 ]. It has been shown that the isoform switch of Ttn in cardiomyocytes is dependent on the function of Rbm20 [ 58 ], which possesses a single central RRM and regulates a large number of heart genes [ 59 ]. Moreover, mutations of both RBM20 and TTN genes in humans cause dilated cardiomyopathy [ 60 , 61 , 62 ].…”

Section: Rbm24 Regulates Muscle Cell Development Through Distinct mentioning

confidence: 99%

RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

Grifone

Shao

Saquet

et al. 2020

Cells

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RNA-binding proteins control the metabolism of RNAs at all stages of their lifetime. They are critically required for the post-transcriptional regulation of gene expression in a wide variety of physiological and pathological processes. Rbm24 is a highly conserved RNA-binding protein that displays strongly regionalized expression patterns and exhibits dynamic changes in subcellular localization during early development. There is increasing evidence that it acts as a multifunctional regulator to switch cell fate determination and to maintain tissue homeostasis. Dysfunction of Rbm24 disrupts cell differentiation in nearly every tissue where it is expressed, such as skeletal and cardiac muscles, and different head sensory organs, but the molecular events that are affected may vary in a tissue-specific, or even a stage-specific manner. Recent works using different animal models have uncovered multiple post-transcriptional regulatory mechanisms by which Rbm24 functions in key developmental processes. In particular, it represents a major splicing factor in muscle cell development, and plays an essential role in cytoplasmic polyadenylation during lens fiber cell terminal differentiation. Here we review the advances in understanding the implication of Rbm24 during development and disease, by focusing on its regulatory roles in physiological and pathological conditions.

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The Emerging Role of the RBM20 and PTBP1 Ribonucleoproteins in Heart Development and Cardiovascular Diseases

Cited by 29 publications

References 158 publications

Identification of biological correlates associated with respiratory failure in COVID-19

Identification of biological correlates associated with respiratory failure in COVID-19

PTBP1 promotes cardiac hypertrophy and diastolic dysfunction by modulating alternative splicing

RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

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