scholarly journals Differential fates of introns in gene expression due to global alternative splicing

2021 ◽  
Author(s):  
Anjani Kumari ◽  
Saam Sedehizadeh ◽  
John David Brook ◽  
Piotr Kozlowski ◽  
Marzena Wojciechowska
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Neuromuscular Disorders ◽  
Regulation Of Gene Expression ◽  
Protein Isoforms ◽  
Circular Rnas ◽  
Surveillance Systems ◽  
Myotonic Dystrophy Type 2 ◽  
New Vision ◽  
And Function

AbstractThe discovery of introns over four decades ago revealed a new vision of genes and their interrupted arrangement. Throughout the years, it has appeared that introns play essential roles in the regulation of gene expression. Unique processing of excised introns through the formation of lariats suggests a widespread role for these molecules in the structure and function of cells. In addition to rapid destruction, these lariats may linger on in the nucleus or may even be exported to the cytoplasm, where they remain stable circular RNAs (circRNAs). Alternative splicing (AS) is a source of diversity in mature transcripts harboring retained introns (RI-mRNAs). Such RNAs may contain one or more entire retained intron(s) (RIs), but they may also have intron fragments resulting from sequential excision of smaller subfragments via recursive splicing (RS), which is characteristic of long introns. There are many potential fates of RI-mRNAs, including their downregulation via nuclear and cytoplasmic surveillance systems and the generation of new protein isoforms with potentially different functions. Various reports have linked the presence of such unprocessed transcripts in mammals to important roles in normal development and in disease-related conditions. In certain human neurological-neuromuscular disorders, including myotonic dystrophy type 2 (DM2), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Duchenne muscular dystrophy (DMD), peculiar processing of long introns has been identified and is associated with their pathogenic effects. In this review, we discuss different mechanisms involved in the processing of introns during AS and the functions of these large sections of the genome in our biology.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

scholarly journals Cellular stressors may alter islet hormone cell proportions by moderation of alternative splicing patterns

2019 ◽  
Vol 28 (16) ◽  
pp. 2763-2774 ◽  
Author(s):  
Nicola Jeffery ◽  
Sarah Richardson ◽  
David Chambers ◽  
Noel G Morgan ◽  
Lorna W Harries
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Regulation Of Gene Expression ◽  
Splicing Factor ◽  
Splicing Regulation ◽  
Messenger Ribonucleic Acid ◽  
Splicing Patterns ◽  
Cellular Stressors

Abstract Changes to islet cell identity in response to type 2 diabetes (T2D) have been reported in rodent models, but are less well characterized in humans. We assessed the effects of aspects of the diabetic microenvironment on hormone staining, total gene expression, splicing regulation and the alternative splicing patterns of key genes in EndoC-βH1 human beta cells. Genes encoding islet hormones [somatostatin (SST), insulin (INS), Glucagon (GCG)], differentiation markers [Forkhead box O1 (FOXO1), Paired box 6, SRY box 9, NK6 Homeobox 1, NK6 Homeobox 2] and cell stress markers (DNA damage inducible transcript 3, FOXO1) were dysregulated in stressed EndoC-βH1 cells, as were some serine arginine rich splicing factor splicing activator and heterogeneous ribonucleoprotein particle inhibitor genes. Whole transcriptome analysis of primary T2D islets and matched controls demonstrated dysregulated splicing for ~25% of splicing events, of which genes themselves involved in messenger ribonucleic acid processing and regulation of gene expression comprised the largest group. Approximately 5% of EndoC-βH1 cells exposed to these factors gained SST positivity in vitro. An increased area of SST staining was also observed ex vivo in pancreas sections recovered at autopsy from donors with type 1 diabetes (T1D) or T2D (9.3% for T1D and 3% for T2D, respectively compared with 1% in controls). Removal of the stressful stimulus or treatment with the AKT Serine/Threonine kinase inhibitor SH-6 restored splicing factor expression and reversed both hormone staining effects and patterns of gene expression. This suggests that reversible changes in hormone expression may occur during exposure to diabetomimetic cellular stressors, which may be mediated by changes in splicing regulation.

scholarly journals The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart

2018 ◽  
Vol 20 (1) ◽  
pp. 102 ◽  
Author(s):  
Justine Habibian ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Electrostatic Interactions ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Protein Activity ◽  
Histone Protein ◽  
Signal Transduction Protein ◽  
And Function

Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.

scholarly journals The emerging role of circular RNAs in breast cancer

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Si-ying Zhou ◽  
Wei Chen ◽  
Su-jin Yang ◽  
Zi-han Xu ◽  
Jia-hua Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Invasion ◽  
Clinical Characteristics ◽  
Circular Rnas ◽  
Rnase R ◽  
New Class ◽  
Regulatory Rnas ◽  
And Function

AbstractBreast cancer (BCa) is one of the most frequently diagnosed cancers and leading cause of cancer deaths among females worldwide. Circular RNAs (circRNAs) are a new class of endogenous regulatory RNAs characterized by circular shape resulting from covalently closed continuous loops that are capable of regulating gene expression at transcription or post-transcription levels. With the unique structures, circRNAs are resistant to exonuclease RNase R and maintain stability more easily than linear RNAs. Recently, an increasing number of circRNAs are discovered and reported to show different expression in BCa and these dysregulated circRNAs were correlated with patients’ clinical characteristics and grade in the progression of BCa. CircRNAs participate in the bioprocesses of carcinogenesis of BCa, including cell proliferation, apoptosis, cell cycle, tumorigenesis, vascularization, cell invasion, migration as well as metastasis. Here we concentrated on biogenesis and function of circRNAs, summarized their implications in BCa and discussed their potential as diagnostic and therapeutic targets for BCa.

scholarly journals Circular RNAs in Cardiovascular Disease: An Overview

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ximin Fan ◽  
Xinyu Weng ◽  
Yifan Zhao ◽  
Wei Chen ◽  
Tianyi Gan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Noncoding Rna ◽  
Essential Role ◽  
Closed Loop ◽  
Regulation Of Gene Expression ◽  
Circular Rna ◽  
Circular Rnas ◽  
Mirna Sponges

Circular RNA (circRNA), a novel type of endogenous noncoding RNA (ncRNA), has become a research hotspot in recent years. CircRNAs are abundant and stably exist in creatures, and they are found with covalently closed loop structures in which they are quite different from linear RNAs. Nowadays, an increasing number of scientists have demonstrated that circRNAs may have played an essential role in the regulation of gene expression, especially acting as miRNA sponges, and have described the potential mechanisms of several circRNAs in diseases, hinting at their clinical therapeutic values. In this review, the authors summarized the current understandings of the biogenesis and properties of circRNAs and their functions and role as biomarkers in cardiovascular diseases.

scholarly journals Comprehensive Identification and Alternative Splicing of Microexons in Drosophila

2021 ◽  
Vol 12 ◽  
Author(s):  
Ting-Lin Pang ◽  
Zhan Ding ◽  
Shao-Bo Liang ◽  
Liang Li ◽  
Bei Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Sex Determination ◽  
Rna Splicing ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Pathway Gene ◽  
Mrna Transcripts ◽  
Bioinformatic Tool ◽  
Alternatively Spliced

Interrupted exons in the pre-mRNA transcripts are ligated together through RNA splicing, which plays a critical role in the regulation of gene expression. Exons with a length ≤ 30 nt are defined as microexons that are unique in identification. However, microexons, especially those shorter than 8 nt, have not been well studied in many organisms due to difficulties in mapping short segments from sequencing reads. Here, we analyzed mRNA-seq data from a variety of Drosophila samples with a newly developed bioinformatic tool, ce-TopHat. In addition to the Flybase annotated, 465 new microexons were identified. Differentially alternatively spliced (AS) microexons were investigated between the Drosophila tissues (head, body, and gonad) and genders. Most of the AS microexons were found in the head and two AS microexons were identified in the sex-determination pathway gene fruitless.

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