scholarly journals Alternative Splicing in Cardiovascular Disease—A Survey of Recent Findings

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1457
Author(s):  
Ena Hasimbegovic ◽  
Victor Schweiger ◽  
Nina Kastner ◽  
Andreas Spannbauer ◽  
Denise Traxler ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Alternative Splicing ◽  
Heart Development ◽  
Circular Rnas ◽  
Specific Expression ◽  
Tissue Specific ◽  
Structural Disease ◽  
Splicing Patterns

Alternative splicing, a driver of posttranscriptional variance, differs from canonical splicing by arranging the introns and exons of an immature pre-mRNA transcript in a multitude of different ways. Although alternative splicing was discovered almost half a century ago, estimates of the proportion of genes that undergo alternative splicing have risen drastically over the last two decades. Deep sequencing methods and novel bioinformatic algorithms have led to new insights into the prevalence of spliced variants, tissue-specific splicing patterns and the significance of alternative splicing in development and disease. Thus far, the role of alternative splicing has been uncovered in areas ranging from heart development, the response to myocardial infarction to cardiac structural disease. Circular RNAs, a product of alternative back-splicing, were initially discovered in 1976, but landmark publications have only recently identified their regulatory role, tissue-specific expression, and transcriptomic abundance, spurring a renewed interest in the topic. The aim of this review is to provide a brief insight into some of the available findings on the role of alternative splicing in cardiovascular disease, with a focus on atherosclerosis, myocardial infarction, heart failure, dilated cardiomyopathy and circular RNAs in myocardial infarction.

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

scholarly journals Troponin: the biomarker of choice for the detection of cardiac injury

2005 ◽  
pp. 1191-1202
Author(s):  
Luciano Babuin ◽  
Allan S. Jaffe
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Acute Myocardial Infarction ◽  
Troponin I ◽  
Cardiac Injury ◽  
Transaminase Activity ◽  
Elevated Troponin ◽  
Critical Issues ◽  
European Society Of Cardiology

It has been known for 50 years that transaminase activity increases in patients with acute myocardial infarction. With the development of creatine kinase (CK), biomarkers of cardiac injury began to take a major role in the diagnosis and management of patients with acute cardiovascular disease. In 2000 the European Society of Cardiology and the American College of Cardiology recognized the pivotal role of biomarkers and made elevations in their levels the “cornerstone” of diagnosis of acute myocardial infarction. At that time, they also acknowledged that cardiac troponin I and T had supplanted CK-MB as the analytes of choice for diagnosis. In this review, we discuss the science underlying the use of troponin biomarkers, how to interpret troponin values properly and how to apply these measurements to patients who present with possible cardiovascular disease. Troponin is the biomarker of choice for the detection of cardiac injury. To use it properly, one must understand how sensitive the specific assay being used is for detecting cardiac injury, the fact that elevated troponin levels are highly specific for cardiac injury and some critical issues related to the basic science of the protein and its measurement. In this article, we review the biology of troponin, characteristics of assays that measure serum troponin levels and how to apply these measurements to patients who present with possible cardiovascular disease. We also discuss other clinical situations in which troponin levels may be elevated.

scholarly journals The complexity of alternative splicing and landscape of tissue-specific expression in lotus (Nelumbo nucifera) unveiled by Illumina- and single-molecule real-time-based RNA-sequencing

DNA Research ◽  
2019 ◽  
Vol 26 (4) ◽  
pp. 301-311 ◽  
Author(s):  
Yue Zhang ◽  
Tonny Maraga Nyong'A ◽  
Tao Shi ◽  
Pingfang Yang
Keyword(s):  
Alternative Splicing ◽  
Real Time ◽  
Single Molecule ◽  
Intron Retention ◽  
Critical Role ◽  
Full Length ◽  
Specific Expression ◽  
Splice Isoforms ◽  
Tissue Specific ◽  
Genomic Studies

Abstract Alternative splicing (AS) plays a critical role in regulating different physiological and developmental processes in eukaryotes, by dramatically increasing the diversity of the transcriptome and the proteome. However, the saturation and complexity of AS remain unclear in lotus due to its limitation of rare obtainment of full-length multiple-splice isoforms. In this study, we apply a hybrid assembly strategy by combining single-molecule real-time sequencing and Illumina RNA-seq to get a comprehensive insight into the lotus transcriptomic landscape. We identified 211,802 high-quality full-length non-chimeric reads, with 192,690 non-redundant isoforms, and updated the lotus reference gene model. Moreover, our analysis identified a total of 104,288 AS events from 16,543 genes, with alternative 3ʹ splice-site being the predominant model, following by intron retention. By exploring tissue datasets, 370 tissue-specific AS events were identified among 12 tissues. Both the tissue-specific genes and isoforms might play important roles in tissue or organ development, and are suitable for ‘ABCE’ model partly in floral tissues. A large number of AS events and isoform variants identified in our study enhance the understanding of transcriptional diversity in lotus, and provide valuable resource for further functional genomic studies.

Alternative promoter usage and alternative splicing contribute to mRNA heterogeneity of mouse monocarboxylate transporter 2

2007 ◽  
Vol 32 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Shelley X. L. Zhang ◽  
Tina R. Searcy ◽  
Yiman Wu ◽  
David Gozal ◽  
Yang Wang
Keyword(s):  
Transcription Factors ◽  
Alternative Splicing ◽  
Alternative Promoter ◽  
Monocarboxylate Transporter ◽  
Specific Expression ◽  
Exon 2 ◽  
Tissue Specific ◽  
Tissue Specific Expression ◽  
Exon 1 ◽  
Promoter Usage

Expression patterns of monocarboxylate transporter 2 (MCT2) display mRNA diversity in a tissue-specific fashion. We cloned and characterized multiple mct2 5′-cDNA ends from the mouse and determined the structural organization of the mct2 gene. We found that transcription of this gene was initiated from five independent genomic regions that spanned >80 kb on chromosome 10, resulting in five unique exon 1 variants (exons 1a, 1b, 1c, 1d, and 1e) that were then spliced to the common exon 2. Alternative splicing of four internal exons (exons AS1, AS2, AS3, and exon 3) greatly increased the complexity of mRNA diversity. While exon 1c was relatively commonly used for transcription initiation in various tissues, other exon 1 variants were used in a tissue-specific fashion, especially exons 1b and 1d that were used exclusively for testis-specific expression. Sequence analysis of 5′-flanking regions upstream of exons 1a, 1b, and 1c revealed the presence of numerous potential binding sites for ubiquitous transcription factors in all three regions and for transcription factors implicated in testis-specific or hypoxia-induced gene expression in the 1b region. Transient transfection assays demonstrated that each of the three regions contained a functional promoter and that the in vitro, cell type-specific activities of these promoters were consistent with the tissue-specific expression pattern of the mct2 gene in vivo. These results indicate that tissue-specific expression of the mct2 gene is controlled by multiple alternative promoters and that both alternative promoter usage and alternative splicing contribute to the remarkable mRNA diversity of the gene.

scholarly journals Design and application of circular RNAs with protein-sponge function

2020 ◽  
Vol 48 (21) ◽  
pp. 12326-12335
Author(s):  
Silke Schreiner ◽  
Anna Didio ◽  
Lee-Hsueh Hung ◽  
Albrecht Bindereif
Keyword(s):  
Alternative Splicing ◽  
Mammalian Cells ◽  
Regulatory Networks ◽  
Rna Binding ◽  
Molecular Medicine ◽  
Circular Rnas ◽  
Ca Repeat ◽  
New Strategy ◽  
Nuclear Ribonucleoprotein ◽  
Splicing Patterns

Abstract Circular RNAs (circRNAs) are a class of noncoding RNAs, generated from pre-mRNAs by circular splicing of exons and functionally largely uncharacterized. Here we report on the design, expression, and characterization of artificial circRNAs that act as protein sponges, specifically binding and functionally inactivating hnRNP (heterogeneous nuclear ribonucleoprotein) L. HnRNP L regulates alternative splicing, depending on short CA-rich RNA elements. We demonstrate that designer hnRNP L-sponge circRNAs with CA-repeat or CA-rich sequence clusters can efficiently and specifically modulate splicing-regulatory networks in mammalian cells, including alternative splicing patterns and the cellular distribution of a splicing factor. This new strategy can in principle be applied to any RNA-binding protein, opening up new therapeutic strategies in molecular medicine.

scholarly journals Tissue-Specific Differences of p53 Inhibition by Mdm2 and Mdm4

2006 ◽  
Vol 26 (1) ◽  
pp. 192-198 ◽  
Author(s):  
Jason D. Grier ◽  
Shunbin Xiong ◽  
Ana C. Elizondo-Fraire ◽  
John M. Parant ◽  
Guillermina Lozano
Keyword(s):  
Heart Failure ◽  
Heart Development ◽  
Direct Evidence ◽  
Critical Number ◽  
Tissue Specific ◽  
Embryonic Lethal ◽  
Proliferation And Apoptosis ◽  
Specific Manner ◽  
Correct Ratio

ABSTRACT The function of the p53 tumor suppressor to inhibit proliferation or initiate apoptosis is often abrogated in tumor cells. Mdm2 and its homolog, Mdm4, are critical inhibitors of p53 that are often overexpressed in human tumors. In mice, loss of Mdm2 or Mdm4 leads to embryonic lethal phenotypes that are completely rescued by concomitant loss of p53. To examine the role of Mdm2 and Mdm4 in a temporal and tissue-specific manner and to determine the relationships of these inhibitors to each other, we generated conditional alleles. We deleted Mdm2 and Mdm4 in cardiomyocytes, since proliferation and apoptosis are important processes in heart development. Mice lacking Mdm2 in the heart were embryonic lethal and showed defects at the time recombination occurred. A critical number of cardiomyocytes were lost by embryonic day 13.5, resulting in heart failure. This phenotype was completely rescued by deletion of p53. Mice lacking Mdm4 in the heart were born at the correct ratio and appeared to be normal. Our studies provide the first direct evidence that Mdm2 can function in the absence of Mdm4 to regulate p53 activity in a tissue-specific manner. Moreover, Mdm4 cannot compensate for the loss of Mdm2 in heart development.

scholarly journals Microarray Expression Profile of Circular RNAs in Heart Tissue of Mice with Myocardial Infarction-Induced Heart Failure

2016 ◽  
Vol 39 (1) ◽  
pp. 205-216 ◽  
Author(s):  
Hong-Jin Wu ◽  
Cheng-Ying Zhang ◽  
Sai Zhang ◽  
Min Chang ◽  
Hong-Yun Wang
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Potential Role ◽  
Expression Patterns ◽  
Heart Tissue ◽  
Circular Rnas ◽  
Global Changes ◽  
Microarray Expression ◽  
Microarray Expression Profile

Background/Aims: Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. This study is aimed to assess the global changes in and characteristics of the transcriptome of circular RNAs (circRNAs) in heart tissue during MI induced heart failure (HF). Methods: Using a post-myocardial infarction (MI) model of HF in mice, we applied microarray assay to examine the transcriptome of circRNAs deregulated in the heart during HF. We confirmed the changes in circRNAs by quantitative PCR. Results: We revealed and confirmed a number of circRNAs that were deregulated during HF, which suggests a potential role of circRNAs in HF. Conclusions: The distinct expression patterns of circulatory circRNAs during HF indicate that circRNAs may actively respond to stress and thus serve as biomarkers of HF diagnosis and treatment.

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