Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts

Verma, Sunil Kumar; Deshmukh, Vaibhav; Nutter, Curtis A.; Jaworski, Elizabeth; Jin, Wenhao; Wadhwa, Lalita; Abata, Joshua; Ricci, Marco; Lincoln, Joy; Martin, James F.; Yeo, G; Kuyumcu‐Martinez, Muge N.

doi:10.1038/srep30896

Cited by 50 publications

(70 citation statements)

References 40 publications

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“…Diabetes also impacts skeletal muscle function causing muscle weakness and atrophy (Andersen et al, 1997;Hernandez-Ochoa & Vanegas, 2015) RBPs are important regulators of cell survival and function, because they have essential roles in fundamental cellular processes such as proliferation, differentiation, and apoptosis (Brinegar & Cooper, 2016;Castello, Fischer, Hentze, & Preiss, 2013;Gerstberger et al, 2014). Dysregulation of RBPs has been observed in a plethora of diseases including cancer (reviewed in Castello et al, 2013;Gerstberger et al, 2014), neurological (reviewed in Cookson, 2017;Donlin-Asp, Rossoll, & Bassell, 2017), and cardiovascular diseases (reviewed in de Bruin, Rabelink, van Zonneveld, & van der Veer, 2017;Nutter et al, 2016;Verma et al, 2016;Xin, Deng, & Fu, 2014). Several RBPs have been associated with the development of diabetes or with diabetic complications (Ben-Haim, Moshitch-Moshkovitz, & Rechavi, 2015;Chu et al, 2008;Gerken et al, 2007;Lyssenko et al, 2008;Rao et al, 2016;Scott et al, 2007;van Hoek et al, 2008;Wood et al, 2016).…”

Section: Rna-binding Proteinsmentioning

confidence: 99%

Emerging roles of RNA‐binding proteins in diabetes and their therapeutic potential in diabetic complications

Nutter

Kuyumcu‐Martinez

2017

WIREs RNA

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Diabetes is a debilitating health care problem affecting 422 million people around the world. Diabetic patients suffer from multisystemic complications that can cause mortality and morbidity. Recent advancements in high-throughput next-generation RNA-sequencing and computational algorithms led to the discovery of aberrant posttranscriptional gene regulatory programs in diabetes. However, very little is known about how these regulatory programs are mis-regulated in diabetes. RNA-binding proteins (RBPs) are important regulators of posttranscriptional RNA networks, which are also dysregulated in diabetes. Human genetic studies provide new evidence that polymorphisms and mutations in RBPs are linked to diabetes. Therefore, we will discuss the emerging roles of RBPs in abnormal posttranscriptional gene expression in diabetes. Questions that will be addressed are: Which posttranscriptional mechanisms are disrupted in diabetes? Which RBPs are responsible for such changes under diabetic conditions? How are RBPs altered in diabetes? How does dysregulation of RBPs contribute to diabetes? Can we target RBPs using RNA-based methods to restore gene expression profiles in diabetic patients? Studying the evolving roles of RBPs in diabetes is critical not only for a comprehensive understanding of diabetes pathogenesis but also to design RNA-based therapeutic approaches for diabetic complications. WIREs RNA 2018, 9:e1459. doi: 10.1002/wrna.1459 This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing Translation > Translation Regulation.

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Section: Rna-binding Proteinsmentioning

confidence: 99%

Emerging roles of RNA‐binding proteins in diabetes and their therapeutic potential in diabetic complications

Nutter

Kuyumcu‐Martinez

2017

WIREs RNA

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“…The RNA binding protein RBFOX2 is critical for heart and skeletal muscle function. Loss of function mutations in RBFOX2 are identified in patients with hypoplastic left heart syndrome (Homsy et al, 2015, Verma et al, 2016b. Low RBFOX2 activity is also associated with heart failure (Wei et al, 2015b) and cardiac complications of diabetes (Nutter et al, 2016, Nutter et al, 2017.…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondria are essential for heart and muscle function and mitochondrial functions diminish in human diseases including heart failure and diabetic hearts (Rosca and Hoppel, 2013). Mitochondrial defects are also implicated in congenital heart defects such as hypoplastic left heart syndrome (Karamanlidis et al, 2011), in which RBFOX2 mutations have been identified (Homsy et al, 2015, Verma et al, 2016b. Although mitochondrial defects have been identified as a pathogenic contributor to the heart diseases in which RBFOX2 is implicated, it is unclear whether RBFOX2 is involved in mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

RBFOX2 is Critical for Maintaining Alternative Polyadenylation Patterns and Mitochondrial Health in Rat Myoblasts

Cao

Jaworski

Rayavara

et al. 2020

Preprint

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The RNA binding protein RBFOX2 is linked to heart and skeletal muscle diseases; yet, RBFOX2-regulated RNA networks have not been systematically identified.Although RBFOX2 has a well-known function in alternative splicing (AS), it is unclear whether RBFOX2 has other roles in RNA metabolism that affect gene expression and function. Utilizing state of the art techniques Poly(A)-ClickSeq (PAC-seq) and nanopore cDNA sequencing, we revealed a new role for RBFOX2 in fine tuning alternative polyadenylation (APA) of pre-mRNAs in myoblasts. We found that depletion of RBFOX2 altered expression of mitochondrial genes. We identified the mitochondrial gene Slc25a4 gene that transports ATP/ADP across inner mitochondrial membrane as a target of RBFOX2. Dissecting how RBFOX2 affects Slc25a4 APA uncovered that RBFOX2 binding motifs near the distal polyadenylation site (PAS) are critical for expression of Slc25a4. Consistent with changes in expression of mitochondrial genes, loss of RBFOX2 altered mitochondrial membrane potential and induced mitochondrial swelling. Our results unveiled a novel role for RBFOX2 in maintaining APA decisions and expression of mitochondrial genes in myoblasts relevant to heart diseases. Keywords: alternative polyadenylation/mitochondria/nanopore sequencing/ poly(A) sequencing/RBFOX2 Non-standard Abbreviations and Acronyms: AS alternative splicing PAC-seq poly(A)-ClickSeq APA alternative polyadenylation KD knock down 3´UTR 3´untranslated region PAS poly(A)-site PAC poly(A)-cluster DPAC differential-poly(A)-clustering dPAS distal poly(A)-site pPAS proximal poly(A)-site ANT1 (Slc25a4) ATP/ADP translocator (mitochondrial) MFN1 Mitofusin

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“…RBFOX family represents a multifunctional group of sequence-specific RNA binding proteins that are critical regulators of splicing in multiple tissues including skeletal muscle, heart, and brain 23,36,37,40,44,[70][71][72][73] . Loss-offunction mutations in RBFOX2 gene have been associated with congenital heart disease in humans [41][42][43] ; whereas RBFOX2 activity in diabetic hearts is inhibited due to upregulation of its dominant negative splice isoform 45,74 . Recently, RBFOX1 and RBFOX2 proteins were shown to compete with MBNL1 for binding to expanded r(CCUG) exp repeats in DM2 but not to r(CUG) exp repeats in DM1 muscle cells 75 .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of a non-muscle RBFOX2 isoform triggers cardiac conduction defects in myotonic dystrophy

Misra¹,

Bangru²,

Lin³

et al. 2019

Preprint

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Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG trinucleotide repeat expansion in the 3′ untranslated region of DMPK gene. Heart dysfunctions occur in nearly 80% of DM1 patients and are the second leading cause of DM1-related deaths. Despite these figures, the mechanisms underlying cardiac-based DM1 phenotypes are unknown. Herein, we report that upregulation of a non-muscle splice isoform of RNA binding protein RBFOX2 in DM1 heart tissue-due to altered splicing factor and microRNA activities-induces cardiac conduction defects in DM1 individuals. Mice engineered to express the non-muscle RBFOX2 isoform in heart via tetracycline-inducible transgenesis, or CRISPR/Cas9-mediated genome editing, reproduced DM1-related cardiac-conduction delay and spontaneous episodes of arrhythmia. Further, by integrating RNA binding with cardiac transcriptome datasets from both DM1 patients and mice expressing the non-muscle RBFOX2 isoform, we identified RBFOX2-driven splicing defects in the voltage-gated sodium and potassium channels, which can alter their electrophysiological properties. Thus, our results uncover a trans-dominant role for an aberrantly expressed RBFOX2 isoform in DM1 cardiac pathogenesis. 3

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Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts

Cited by 50 publications

References 40 publications

Emerging roles of RNA‐binding proteins in diabetes and their therapeutic potential in diabetic complications

Emerging roles of RNA‐binding proteins in diabetes and their therapeutic potential in diabetic complications

RBFOX2 is Critical for Maintaining Alternative Polyadenylation Patterns and Mitochondrial Health in Rat Myoblasts

Overexpression of a non-muscle RBFOX2 isoform triggers cardiac conduction defects in myotonic dystrophy

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