Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes.
Curtis A Nutter, Elizabeth A Jaworski, Sunil K Verma, Vaibhav Deshmukh, Qiongling Wang, Olga B Botvinnik, Mario J Lozano, Ismail J Abass, Talha Ijaz, Allan R Brasier, Nisha J Garg, Xander H T Wehrens, Gene W Yeo, Muge N Kuyumcu-Martinez
Cell reports · 2016 · Vol. 15 (10) · pp. 2200-2213
Abstract
Alternative splicing (AS) defects that adversely affect gene expression and function have been identified in diabetic hearts; however, the mechanisms responsible are largely unknown. Here, we show that the RNA-binding protein RBFOX2 contributes to transcriptome changes under diabetic conditions. RBFOX2 controls AS of genes with important roles in heart function relevant to diabetic cardiomyopathy. RBFOX2 protein levels are elevated in diabetic hearts despite low RBFOX2 AS activity. A dominant-negative (DN) isoform of RBFOX2 that blocks RBFOX2-mediated AS is generated in diabetic hearts. DN RBFOX2 interacts with wild-type (WT) RBFOX2, and ectopic expression of DN RBFOX2 inhibits AS of RBFOX2 targets. Notably, DN RBFOX2 expression is specific to diabetes and occurs at early stages before cardiomyopathy symptoms appear. Importantly, DN RBFOX2 expression impairs intracellular calcium release in cardiomyocytes. Our results demonstrate that RBFOX2 dysregulation by DN RBFOX2 is an early pathogenic event in diabetic hearts.
Linked datasets 1
Transcriptome-wide mRNA alterations in Streptozotocin induced Type I diabetic mouse heart
Mus musculus
10 data files
| File | Type | Size |
|---|---|---|
| 11_NoIndex_L001_R1_001.fastq.gz | RNA-Seq | 10.9 GB |
| 15_NoIndex_L002_R1_001.fastq.gz | RNA-Seq | 12.3 GB |
| 24_NoIndex_L003_R1_001.fastq.gz | RNA-Seq | 10.8 GB |
| 5407_NoIndex_L007_R1_001.fastq.gz | RNA-Seq | 12.3 GB |
| 5408_NoIndex_L008_R1_001.fastq.gz | RNA-Seq | 16.4 GB |
| SRR3499912_GSM2132563 | RNA-Seq | 12.3 GB |
| SRR3499913_GSM2132564 | RNA-Seq | 16.4 GB |
| SRR3499914_GSM2132565 | RNA-Seq | 10.9 GB |
| SRR3499915_GSM2132566 | RNA-Seq | 12.3 GB |
| SRR3499916_GSM2132567 | RNA-Seq | 10.8 GB |
Analysis pipelines 1
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE80664 Data Processing geo_data_processing | — | 9 | GSE80664 |
Funding 10 grants
| Grant | Funder |
|---|---|
| R01 HG004659 | NHGRI NIH HHS (United States) |
| R01 NS075449 | NINDS NIH HHS (United States) |
| UL1 TR001439 | NCATS NIH HHS (United States) |
| F30 HL128036 | NHLBI NIH HHS (United States) |
| R41 HL129570 | NHLBI NIH HHS (United States) |
| R01 HL091947 | NHLBI NIH HHS (United States) |
| UL1 TR000071 | NCATS NIH HHS (United States) |
| R01 HL089598 | NHLBI NIH HHS (United States) |
| P30 ES006676 | NIEHS NIH HHS (United States) |
| R01 HL117641 | NHLBI NIH HHS (United States) |