TY - JOUR
T1 - CELF1 contributes to aberrant alternative splicing patterns in the type 1 diabetic heart
AU - Belanger, Karry Anne
AU - Nutter, Curtis A.
AU - Li, Jin
AU - Tasnim, Sadia
AU - Liu, Peiru
AU - Yu, Peng
AU - Kuyumcu-Martinez, Muge N.
N1 - Funding Information:
We thank Kuyumcu-Martinez lab members and Dr. Eric Wagner for critically reading the manuscript and Dr. Mariano Garcia-Blanco for providing the Ad-GFP splicing reporter. 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 NIH. This work was also supported by startup funding to P.Y. from the ECE department and Engineering Experiment Station/Dwight Look College of Engineering; by funding from TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering (CBGSE) , by TEES seed grant; and by CAPES Research Grant Program at Texas A&M University .
PY - 2018/9/18
Y1 - 2018/9/18
N2 - Dysregulated alternative splicing (AS) that contributes to diabetes pathogenesis has been identified, but little is known about the RNA binding proteins (RBPs) involved. We have previously found that the RBP CELF1 is upregulated in the diabetic heart; however, it is unclear if CELF1 contributes to diabetes-induced AS changes. Utilizing genome wide approaches, we identified extensive changes in AS patterns in Type 1 diabetic (T1D) mouse hearts. We discovered that many aberrantly spliced genes in T1D hearts have CELF1 binding sites. CELF1-regulated AS affects key genes within signaling pathways relevant to diabetes pathogenesis. Disruption of CELF1 binding sites impairs AS regulation by CELF1. In sum, our results indicate that CELF1 target RNAs are aberrantly spliced in the T1D heart leading to abnormal gene expression. These discoveries pave the way for targeting RBPs and their RNA networks as novel therapies for cardiac complications of diabetes.
AB - Dysregulated alternative splicing (AS) that contributes to diabetes pathogenesis has been identified, but little is known about the RNA binding proteins (RBPs) involved. We have previously found that the RBP CELF1 is upregulated in the diabetic heart; however, it is unclear if CELF1 contributes to diabetes-induced AS changes. Utilizing genome wide approaches, we identified extensive changes in AS patterns in Type 1 diabetic (T1D) mouse hearts. We discovered that many aberrantly spliced genes in T1D hearts have CELF1 binding sites. CELF1-regulated AS affects key genes within signaling pathways relevant to diabetes pathogenesis. Disruption of CELF1 binding sites impairs AS regulation by CELF1. In sum, our results indicate that CELF1 target RNAs are aberrantly spliced in the T1D heart leading to abnormal gene expression. These discoveries pave the way for targeting RBPs and their RNA networks as novel therapies for cardiac complications of diabetes.
KW - Alternative splicing
KW - CELF1
KW - Diabetic heart
KW - RNA binding proteins
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U2 - 10.1016/j.bbrc.2018.08.126
DO - 10.1016/j.bbrc.2018.08.126
M3 - Article
C2 - 30158053
AN - SCOPUS:85052863867
VL - 503
SP - 3205
EP - 3211
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 4
ER -