title: Reactivation of fetal splicing programs in diabetic hearts is mediated by protein kinase C signaling.
abstract: Diabetic cardiomyopathy is one of the complications of diabetes that eventually leads to heart failure and death. Aberrant activation of PKC signaling contributes to diabetic cardiomyopathy by mechanisms that are poorly understood. Previous reports indicate that PKC is implicated in alternative splicing regulation. Therefore, we wanted to test whether PKC activation in diabetic hearts induces alternative splicing abnormalities. Here, using RNA sequencing we identified a set of 22 alternative splicing events that undergo a developmental switch in splicing, and we confirmed that splicing reverts to an embryonic pattern in adult diabetic hearts. This network of genes has important functions in RNA metabolism and in developmental processes such as differentiation. Importantly, PKC isozymes α/β control alternative splicing of these genes via phosphorylation and up-regulation of the RNA-binding proteins CELF1 and Rbfox2. Using a mutant of CELF1, we show that phosphorylation of CELF1 by PKC is necessary for regulation of splicing events altered in diabetes. In summary, our studies indicate that activation of PKCα/β in diabetic hearts contributes to the genome-wide splicing changes through phosphorylation and up-regulation of CELF1/Rbfox2 proteins. These findings provide a basis for PKC-mediated cardiac pathogenesis under diabetic conditions.
authors.affiliation: From the Departments of Biochemistry and Molecular Biology and.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Verma
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Deshmukh
authors.forename: Patrick
authors.initials: P
authors.lastname: Liu
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Nutter
authors.forename: Rosario
authors.initials: R
authors.lastname: Espejo
authors.forename: Ming-Lung
authors.initials: ML
authors.lastname: Hung
authors.forename: Guey-Shin
authors.initials: GS
authors.lastname: Wang
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.forename: Muge N
authors.initials: MN
authors.lastname: Kuyumcu-Martinez
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005333:Fetus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D064546:Protein Kinase C beta / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D016601:RNA-Binding Proteins; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha
keywords: Alternative Splicing; Diabetes; Heart Development; Protein Kinase C (PKC); RNA-binding Protein; Signal Transduction