TY - JOUR
T1 - A developmentally regulated spliced variant of PTBP1 is upregulated in type 1 diabetic hearts
AU - Belanger, Karry Anne
AU - Nutter, Curtis A.
AU - Li, Jin
AU - Yu, Peng
AU - Kuyumcu-Martinez, Muge N.
N1 - Funding Information:
We thank Dr. Mariano Garcia-Blanco for providing the PTBP1 antibody and Flp-in T-REx 293 cells. We thank Dr. Benjamin J. Blencowe for the Triple flag-tagged human PTBP1+ex9 and human PTBP1Δex9 pcDNA5/FRT/TO expression vectors. This work was supported, in part, by an American Heart Association Grant [ 15GRNT22830010 ]; UTMB Department of Biochemistry and Molecular Biology Bridging funds ; and a grant from the National Institutes of Health/ National Heart Lung Blood Institute [ 1R01HL135031 ] to M.N.K-M. The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NHLBI of NIH. This work was also supported by startup funding to P.Y. from the ECE department and Texas A&M Engineering Experiment Station/Dwight Look College of Engineering at Texas A&M University ; by funding from TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas A&M University , by TEES seed grant; and by Texas A&M University-CAPES Research Grant Program .
Funding Information:
We thank Dr. Mariano Garcia-Blanco for providing the PTBP1 antibody and Flp-in T-REx 293 cells. We thank Dr. Benjamin J. Blencowe for the Triple flag-tagged human PTBP1+ex9 and human PTBP1Δex9 pcDNA5/FRT/TO expression vectors. This work was supported, in part, by an American Heart Association Grant [15GRNT22830010]; UTMB Department of Biochemistry and Molecular Biology Bridging funds; and a grant from the National Institutes of Health/ National Heart Lung Blood Institute [1R01HL135031] to M.N.K-M. The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NHLBI of NIH. This work was also supported by startup funding to P.Y. from the ECE department and Texas A&M Engineering Experiment Station/Dwight Look College of Engineering at Texas A&M University; by funding from TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas A&M University, by TEES seed grant; and by Texas A&M University-CAPES Research Grant Program.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2019/2/5
Y1 - 2019/2/5
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Diabetic heart
KW - PTBP1
KW - RNA binding proteins
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U2 - 10.1016/j.bbrc.2018.12.150
DO - 10.1016/j.bbrc.2018.12.150
M3 - Article
C2 - 30594394
AN - SCOPUS:85059044647
SN - 0006-291X
VL - 509
SP - 384
EP - 389
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -