RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts

Cao, Jun; Verma, Sunil Kumar; Jaworski, Elizabeth; Mohan, Stephanie; Nagasawa, Chloe; Rayavara, Kempaiah; Sooter, Amanda; Miller, Sierra; Holcomb, Richard J.; Powell, Mason J.; Ji, Ping; Elrod, Nathan D.; Yildirim, E.; Wagner, Eric J.; Popov, Vsevolod L.; Garg, Nisha; Routh, Andrew; Kuyumcu‐Martinez, Muge N.

doi:10.1016/j.celrep.2021.109910

Cited by 14 publications

(4 citation statements)

References 65 publications

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“…The independence of these two abnormalities seems likely as we observed decreased expression and alternative splicing of both sarcomere and mitochondrial transcripts in rbfox -deficient zebrafish hearts. Consistent with this finding, a previous report documented decreased expression of sarcomere and mitochondrial components in Rbfox2-depleted rat myoblasts due to alternative polyadenylation 33 . However, conditional knock-out of Rbfox2 in the embryonic mouse heart was linked to changes in alternative splicing of transcripts involved in cell adhesion to the extra-cellular matrix 14 , a process not readily identified in our datasets.…”

Section: Discussionsupporting

confidence: 88%

Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome

Huang

Akerberg²,

Zhang³

et al. 2022

Nat Commun

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Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta. Prevailing paradigm suggests that HLHS is a multigenic disease of co-occurring phenotypes. Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene linked to HLHS in humans, display cardiovascular defects overlapping those in HLHS patients including ventricular, valve, and aortic deficiencies. In contrast to current models, we demonstrate that these structural deficits arise secondary to impaired pump function as these phenotypes are rescued when Rbfox is specifically expressed in the myocardium. Mechanistically, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 mRNA restores cardiovascular development in rbfox mutant zebrafish, while HLHS-linked RBFOX2 variants fail to rescue. This work supports an emerging paradigm for HLHS pathogenesis that centers on myocardial intrinsic defects.

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Section: Discussionsupporting

confidence: 88%

Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome

Huang

Akerberg²,

Zhang³

et al. 2022

Nat Commun

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“…Similarly, in human embryonic stem cells and cardioids, Rbpms controls a specialized mRNA translation circuit to specify cardiac mesoderm and promote cardiac morphogenesis [ 105 ]. In H9c2 rat myoblasts, the deletion of Rbfox2 affects the expression of contractile and mitochondrial genes via alternative polyadenylation [ 106 ]. Igf2bp2 generally functions as an m6A reader and regulates mRNA stability [ 89 ].…”

Section: Discussionmentioning

confidence: 99%

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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“…The depletion of RBFOX2 adversely affects mitochondrial health by Slc25a4 inhibition. Slc25a4 gene encodes for ATP/ADP translocator 1 (ANT1), which is critical for energy production in the mitochondria [ 37 ]. It has been shown that ablation of Slc25a4 (ANT1) in mice exhibited a severe defect in coupled mitochondrial respiration [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA-Profile-Based Screening of Extracellular Vesicles Released from Brain Endothelial Cells after Oxygen–Glucose Deprivation

Zou²,

Liu³

et al. 2022

Brain Sciences

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Brain microvascular endothelial cells (BMECs) linked by tight junctions play important roles in cerebral ischemia. Intercellular signaling via extracellular vesicles (EVs) is an underappreciated mode of cell–cell crosstalk. This study aims to explore the potential function of long noncoding RNAs (lncRNAs) in BMECs’ secreted EVs. We subjected primary human and rat BMECs to oxygen and glucose deprivation (OGD). EVs were enriched for RNA sequencing. A comparison of the sequencing results revealed 146 upregulated lncRNAs and 331 downregulated lncRNAs in human cells and 1215 upregulated lncRNAs and 1200 downregulated lncRNAs in rat cells. Next, we analyzed the genes that were coexpressed with the differentially expressed (DE) lncRNAs on chromosomes and performed Gene Ontology (GO) and signaling pathway enrichment analyses. The results showed that the lncRNAs may play roles in apoptosis, the TNF signaling pathway, and leukocyte transendothelial migration. Next, three conserved lncRNAs between humans and rats were analyzed and confirmed using PCR. The binding proteins of these three lncRNAs in human astrocytes were identified via RNA pulldown and mass spectrometry. These proteins could regulate mRNA stability and translation. Additionally, the lentivirus was used to upregulate them in human microglial HMC3 cells. The results showed NR_002323.2 induced microglial M1 activation. Therefore, these results suggest that BMECs’ EVs carry the lncRNAs, which may regulate gliocyte function after cerebral ischemia.

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RBFOX2 is critical for maintaining alternative polyadenylation patterns and mitochondrial health in rat myoblasts

Cited by 14 publications

References 65 publications

Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome

Intrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome

RNA-Binding Proteins in Cardiomyopathies

LncRNA-Profile-Based Screening of Extracellular Vesicles Released from Brain Endothelial Cells after Oxygen–Glucose Deprivation

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