Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes

Nutter, Curtis A.; Jaworski, Elizabeth; Verma, Sunil Kumar; Deshmukh, Vaibhav; Wang, Qiongling; Botvinnik, Olga; Lozano, M.; Abass, Ismail J.; Ijaz, Talha; Brasier, Allan R.; Garg, Nisha; Wehrens, Xander H.T.; Yeo, G; Kuyumcu‐Martinez, Muge N.

doi:10.1016/j.celrep.2016.05.002

Cited by 63 publications

(117 citation statements)

References 46 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…Finally, misregulation or misexpression of both CELF2 and RBFOX2 have been implicated as contributors to human disease including cancer, muscular dystrophies, heart failure, and Type 1 diabetes (Kuyumcu-Martinez et al 2007;Cooper et al 2009;Verma et al 2013;Nutter et al 2016). Our finding of mutual antagonism between these proteins suggests that disease-relevant splicing attributed previously to CELF2 or RBFOX2 may also be impacted by altered expression of the other.…”

Section: Implications Of Celf2/rbfox2 Antagonism For Understanding Humentioning

confidence: 54%

“…5E). RBFOX2 has been shown to be dysregulated in the hearts of diabetic patients and a mouse model of Type I diabetes (T1D), where it forms a dominant negative version of the protein, leading to a number of splicing changes (Nutter et al 2016). CELF1 has also been shown to be up-regulated in diabetic hearts via PKC signaling (Kuyumcu- Martinez et al 2007;Verma et al 2013), but the global consequences of this have not been examined.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

See 1 more Smart Citation

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

View full text Add to dashboard Cite

Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic coregulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets, including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these coregulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues, including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, Drosophila, and Caenorhabditis elegans suggests this antagonism is conserved throughout evolution.

show abstract

Section: Implications Of Celf2/rbfox2 Antagonism For Understanding Humentioning

confidence: 54%

Section: Wwwgenomeorgmentioning

confidence: 99%

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Nutter et al [23] recently suggested that high concentration of a protein RBFOX2 in cardiac cells can interfere with many important molecular mechanisms. In consequence, leading to inappropriate protein and calcium exchange in cardiomyocytes.…”

Section: New Reports On Pathogenesis Of Diabetic Cardiomyopathymentioning

confidence: 99%

Can the onset of heart failure be delayed by treating diabetic cardiomyopathy?

Marcinkiewicz

Ostrowski

Drzewoski

2017

Diabetol Metab Syndr

View full text Add to dashboard Cite

The pathophysiology of diabetic cardiomyopathy (DC) is not fully understood. This frequently undiagnosed complication of chronic hyperglycemia leads to heart failure (HF). However, it is suggested that an appropriate metabolic control of diabetes at an early stage of this deleterious disease, is able to inhibit the development and progression of DC to HF. Recently, it has been postulated that myocardial ischaemia plays an important role in the development of this pathology. Results of the antianginal pharmacological treatment and revascularization are unsatisfactory and reveal a gap in our knowledge and current approaches to treating DC. Most recent studies emphasize the ischaemic component of DC as a key target for therapeutic strategies, which could change its unfavorable history. More stress is put on an early diagnosis of coronary artery disease (CAD), promoting prompt revascularization. Choosing the accurate time of surgical revascularization, with the inclusion of the metabolic background, can ensure complete revascularization with better prognosis. This review will focus on the complexity of DC and summarize contemporary knowledge of treatment strategies for patients with diabetes and CAD.

show abstract

Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes

Cited by 63 publications

References 46 publications

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

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

Can the onset of heart failure be delayed by treating diabetic cardiomyopathy?

Contact Info

Product

Resources

About