A developmentally regulated spliced variant of PTBP1 is upregulated in type 1 diabetic hearts.
Alternative Splicing
Animals
CELF1 Protein
/ genetics
Diabetes Mellitus, Experimental
/ chemically induced
Diabetic Cardiomyopathies
/ chemically induced
Gene Expression Profiling
Gene Expression Regulation, Developmental
HEK293 Cells
Heterogeneous-Nuclear Ribonucleoproteins
/ genetics
Humans
Mice
Mice, Inbred NOD
Myocardium
/ metabolism
Polypyrimidine Tract-Binding Protein
/ genetics
Protein Binding
RNA Splicing Factors
/ genetics
Signal Transduction
Streptozocin
Transcriptional Activation
Alternative splicing
Diabetic heart
PTBP1
RNA binding proteins
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
05 02 2019
05 02 2019
Historique:
received:
12
12
2018
accepted:
20
12
2018
pubmed:
31
12
2018
medline:
23
10
2019
entrez:
31
12
2018
Statut:
ppublish
Résumé
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) PTBP1 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.
Identifiants
pubmed: 30594394
pii: S0006-291X(18)32819-5
doi: 10.1016/j.bbrc.2018.12.150
pmc: PMC6330148
mid: NIHMS1517481
pii:
doi:
Substances chimiques
CELF1 Protein
0
CELF1 protein, mouse
0
Heterogeneous-Nuclear Ribonucleoproteins
0
Ptbp1 protein, mouse
0
RNA Splicing Factors
0
Rbfox2 protein, mouse
0
Polypyrimidine Tract-Binding Protein
139076-35-0
Streptozocin
5W494URQ81
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
384-389Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL135031
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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