A developmentally regulated spliced variant of PTBP1 is upregulated in type 1 diabetic hearts

被引:12
|
作者
Belanger, KarryAnne [1 ]
Nutter, Curtis A. [2 ,3 ]
Li, Jin [4 ,5 ]
Yu, Peng [4 ,5 ]
Kuyumcu-Martinez, Muge N. [1 ,6 ,7 ]
机构
[1] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA
[2] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Ctr NeuroGenet, Gainesville, FL 32610 USA
[3] Univ Florida, Coll Med, Genet Inst, Gainesville, FL 32610 USA
[4] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA
[5] Texas A&M Univ, TEES AgriLife Ctr Bioinformat & Genom Syst Engn, College Stn, TX 77843 USA
[6] Univ Texas Med Branch, Dept Neurosci Cell Biol & Anat, Galveston, TX 77555 USA
[7] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA
基金
美国国家卫生研究院;
关键词
Diabetic heart; PTBP1; Alternative splicing; RNA binding proteins; TRACT BINDING-PROTEIN; PRE-MESSENGER-RNA; ANTAGONISTIC REGULATION; CARDIAC-HYPERTROPHY; EXON; 6B; CELF; REPRESSION; EXPRESSION; MBNL; PATHOGENESIS;
D O I
10.1016/j.bbrc.2018.12.150
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alternative splicing (AS) is dysregulated in Type 1 diabetic (T1D) hearts but mechanisms responsible are unclear. Here, we provide evidence that the RNA binding protein (RBP) PIBP1 is modulated in adult T1D hearts contributing to AS changes. We show that a spliced variant of PTBP1 that is highly expressed in normal newborn mouse hearts is aberrantly expressed in adult T1D mouse hearts. Comparing known PTBP1-target datasets to our T1D mouse transcriptome datasets, we discovered a group of genes with PTBP1 binding sites in their pre-mRNAs that are differentially spliced in T1D mouse hearts. We demonstrated that inducible expression of diabetes-induced PTBP1 spliced variant has less repressive splicing function. Notably, PTBP1 regulates AS of some of its targets antagonistically to RBFOX2. In sum, our results indicate that diabetic conditions disrupt developmental regulation of PTBP1 leading to differential AS of PTBP1 target genes. Identification of PTBP1 and PTBP1-regulated RNA networks can provide RNA-based therapies for the treatment of diabetes cardiac complications. (C) 2018 Elsevier Inc. All rights reserved.
引用
收藏
页码:384 / 389
页数:6
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