NDLI: Genome-wide analysis revealed the dysregulation of RNA binding protein-correlated alternative splicing events in myocardial ischemia reperfusion injury

Content Provider	Springer Nature : BioMed Central
Author	Ma, Ning Xu, Hao Zhang, Weihua Sun, Xiaoke Guo, Ruiming Liu, Donghai Zhang, Liang Liu, Yang Zhang, Jian Qiao, Chenhui Chen, Dong Luo, Ailing Bai, Jingyun
Abstract	Background Myocardial ischemia reperfusion injury (MIRI), the tissue damage which is caused by the returning of blood supply to tissue after a period of ischemia, greatly reduces the therapeutic effect of treatment of myocardial infarction. But the underlying functional mechanisms of MIRI are still unclear. Methods We constructed mouse models of MIRI, extracted injured and healthy myocardial tissues, and performed transcriptome sequencing experiments (RNA-seq) to systematically investigate the dysregulated transcriptome of MIRI, especially the alternative splicing (AS) regulation and RNA binding proteins (RBPs). Selected RBPs and MIRI-associated AS events were then validated by RT-qPCR experiments. Results The differentially expressed gene (DEG) analyses indicated that transcriptome profiles were changed by MIRI and that DEGs’ enriched functions were consistent with MIRI’s dysregulated pathways. Furthermore, the AS profile was synergistically regulated and showed clear differences between the mouse model and the healthy samples. The exon skipping events significantly increased in MIRI model samples, while the opposite cassette exon events significantly decreased. According to the functional analysis, regulated alternative splicing genes (RASGs) were enriched in protein transport, cell division /cell cycle, RNA splicing, and endocytosis pathways, which were associated with the development of MIRI. Meanwhile, 493 differentially expressed RBPs (DE RBPs) were detected, most of which were correlated with the changed ratios of AS events. In addition, nine DE RBP genes were validated, including Eif5, Pdia6, Tagln2, Vasp, Zfp36l2, Grsf1, Idh2, Ndrg2, and Uqcrc1. These nine DE RBPs were correlated with RASGs enriched in translation process, cell growth and division, and endocytosis pathways, highly consistent with the functions of all RASGs. Finally, we validated the AS ratio changes of five regulated alternative splicing events (RASEs) derived from important regulatory genes, including Mtmr3, Cdc42, Cd47, Fbln2, Vegfa, and Fhl2. Conclusion Our study emphasized the critical roles of the dysregulated AS profiles in MIRI development, investigated the potential functions of MIRI-associated RASGs, and identified regulatory RBPs involved in AS regulation. We propose that the identified RASEs and RBPs could serve as important regulators and potential therapeutic targets in MIRI treatment in the future.
Related Links	https://bmcmedgenomics.biomedcentral.com/counter/pdf/10.1186/s12920-023-01706-5.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	17558794
DOI	10.1186/s12920-023-01706-5
Journal	BMC Medical Genomics
Issue Number	1
Volume Number	16
Language	English
Publisher	BioMed Central
Publisher Date	2023-10-19
Access Restriction	Open
Subject Keyword	Human Genetics Microarrays Gene Expression MIRI RNA-seq Alternative splicing RNA binding protein Correlation network
Content Type	Text
Resource Type	Article
Subject	Genetics (clinical) Genetics
Journal Impact Factor	2.1/2023
5-Year Journal Impact Factor	2.5/2023

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