scholarly journals Mature Neurons sensitivity to oxidative stress is epigenetically programmed by alternative splicing and mRNA stability

2021 ◽  
Author(s):  
Zhou Yuan ◽  
Sherif Rashad ◽  
Teiji Tominaga ◽  
Kuniyasu Niizuma
Keyword(s):  
Oxidative Stress ◽  
Alternative Splicing ◽  
Neuronal Differentiation ◽  
Mrna Stability ◽  
Intron Retention ◽  
Transcriptional Level ◽  
Epigenetic Changes ◽  
Mrna Isoforms ◽  
Functional Changes ◽  
Mature Neurons

Neuronal differentiation is a complex process that entails extensive morphological, transcriptional, metabolic, and functional changes that dictate neuronal lineage commitment. Much less understood is the role that epigenetic and epi-transcriptional reprogramming plays in the process of neuronal differentiation and maturation. To depict the whole landscape of transcriptomics and epigenetic changes during neuronal differentiation and maturation, we differentiated SH-SY5Y cells and performed RNA sequencing on differentiated and undifferentiated cells. 728 differentially expressed genes (DEGs) enriched in synaptic signaling and cell morphogenesis pathways were observed. Moreover, transcriptome-wide mRNA stability profiling revealed that genes with altered stability were exceptionally enriched for redox homeostasis pathways. Mature neurons are known to be highly sensitive to oxidative stress, which is crucial in the pathophysiology of neurodegenerative disease. Our results suggest that this heightened sensitivity is regulated at the mRNA stability level (i.e., epigenetic) rather than at the transcriptional level. Alternative splicing analysis revealed the exon skipping and alternative mRNA isoforms enriched for morphogenesis related pathway. Alternatively, alternative 5 and 3 prime splicing site, intron retention and mutually exclusive exon events exclusively clustered in the translation and translation initiation pathways, suggesting the potential effect of alternative splicing on translation following neuronal maturation. Splice motif analysis revealed enriched motifs for RBPs that regulate various splice types and can be further correlated to distinct phenotypical changes during neuronal differentiation and maturation. Here we present an extensive exploration of the transcriptional and epigenetic changes and their potential association with the process of neuronal differentiation, providing a new insight into understanding the molecular mechanism of neuronal function and behavior.

scholarly journals Transcriptome Analysis of Alternative Splicing Events Induced by Arbuscular Mycorrhizal Fungi (Rhizophagus irregularis) in Pea (Pisum sativum L.) Roots

Plants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1700
Author(s):  
Evgeny A. Zorin ◽  
Alexey M. Afonin ◽  
Olga A. Kulaeva ◽  
Emma S. Gribchenko ◽  
Oksana Y. Shtark ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Pisum Sativum ◽  
Mycorrhizal Fungi ◽  
Intron Retention ◽  
Protein A ◽  
Fine Tuning ◽  
Mrna Isoforms ◽  
Pisum Sativum L ◽  
Mycorrhizal Roots

Alternative splicing (AS), a process that enables formation of different mRNA isoforms due to alternative ways of pre-mRNA processing, is one of the mechanisms for fine-tuning gene expression. Currently, the role of AS in symbioses formed by plants with soil microorganisms is not fully understood. In this work, a comprehensive analysis of the transcriptome of garden pea (Pisum sativum L.) roots in symbiosis with arbuscular mycorrhiza was performed using RNAseq and following bioinformatic analysis. AS profiles of mycorrhizal and control roots were highly similar, intron retention accounting for a large proportion of the observed AS types (67%). Using three different tools (SUPPA2, DRIMSeq and IsoformSwitchAnalyzeR), eight genes with AS events specific for mycorrhizal roots of pea were identified, among which four were annotated as encoding an apoptosis inhibitor protein, a serine/threonine-protein kinase, a dehydrodolichyl diphosphate synthase, and a pre-mRNA-splicing factor ATP-dependent RNA helicase DEAH1. In pea mycorrhizal roots, the isoforms of these four genes with preliminary stop codons leading to a truncated ORFs were up-regulated. Interestingly, two of these four genes demonstrating mycorrhiza-specific AS are related to the process of splicing, thus forming parts of the feedback loops involved in fine-tuning of gene expression during mycorrhization.

scholarly journals Alternative Splicing in Heat Shock Protein Transcripts as a Mechanism of Cell Adaptation in Trichophyton rubrum

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1206 ◽  
Author(s):  
Neves-da-Rocha ◽  
Bitencourt ◽  
Oliveira ◽  
Sanches ◽  
Rossi ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Heat Shock ◽  
Expression Profile ◽  
Trichophyton Rubrum ◽  
Current Knowledge ◽  
Intron Retention ◽  
Expression Patterns ◽  
Hsp90 Inhibition ◽  
Mrna Isoforms ◽  
Cell Adaptation

Heat shock proteins (HSPs) are involved in critical processes like host tissue invasion, resistance, and pathogenicity in dermatophytes. RNA-Seq analysis of Trichophyton rubrum exposed to undecanoic acid (UDA) revealed intron retention events in HSP transcripts. Because HSPs are modulated in response to various stimuli and as alternative splicing (AS) can result in a broad diversity in the proteome of eukaryotic cells, our objective was to confirm the aforementioned retention events, investigating their consequences and extent. Furthermore, we aimed to determine: (1) the expression profile of HSP genes in an infection-like scenario and (2) the importance of Hsp90 for the keratinolytic potential of T. rubrum. RT and qPCR analyses comparing the exposure to UDA and terbinafine (TRB) confirmed the presence of two mRNA isoforms of the hsp7-like gene, with distinct expression patterns in response to UDA and TRB. The HSP expression profile revealed two upregulated, three downregulated, and four unmodulated transcripts; Hsp90 inhibition by 17-AAG resulted in a significant decrease in keratinolytic potential at 37 °C. Altogether, these results broaden the current knowledge on the importance of HSP-mediated pathways for cell adaptation and other aspects of dermatophyte biology, indicating that HSP network proteins can be potential targets for antifungal therapy.

scholarly journals Intragenic epigenetic changes modulate NCAM alternative splicing in neuronal differentiation

2013 ◽  
Vol 32 (16) ◽  
pp. 2264-2274 ◽  
Author(s):  
Ignacio E Schor ◽  
Ana Fiszbein ◽  
Ezequiel Petrillo ◽  
Alberto R Kornblihtt
Keyword(s):  
Alternative Splicing ◽  
Neuronal Differentiation ◽  
Epigenetic Changes

scholarly journals Genome-wide mapping of alternative splicing in the elite wheat cultivar Xiaoyan 6

2020 ◽  
Author(s):  
Hude Mao ◽  
Jin Zhang ◽  
Lijian Guo ◽  
Qing Chi ◽  
Fangming Mei ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Seed Development ◽  
Developmental Stages ◽  
Wheat Cultivar ◽  
Intron Retention ◽  
Draft Genome ◽  
Gc Content ◽  
Grain Filling ◽  
Transcriptional Level ◽  
Regulation Mechanism

Abstract Background: Triticum aestivum, or common wheat, is a globally important cereal crop. Alternative splicing (AS) is an important post-transcriptional regulation mechanism in higher eukaryotes, but the knowledge of AS in wheat is limited at present. Results: In this study, we performed AS mapping from the elite, high-yielding wheat cultivar Xiaoyan 6. We identified 18,960 and 25,133 novel protein-coding genes and transcript models that were not annotated in the draft genome of wheat cultivar Chinese Spring. We also found that 18,868 genes were alternatively spliced, and classified four major AS types, including alternative acceptor sites (AA), intron retention (IR), alternative donor sites (AD), and exon skipping (ES). Further analysis determined that differences in the AS frequency and AS types displayed a positive correlation with exon number and intron length and were negatively correlated with the GC content, but were not correlated with gene transcriptional level. Furthermore, we identified 2,737 seed-specific AS genes in wheat cultivar Xiaoyan 6, and demonstrated that the number of AS genes in the grain decreased with seed development, suggesting that the earlier developmental stages are more important and complex than are the later stages. In addition, the grain-specific AS genes that were ubiquitously significantly up-regulated during seed development were associated with metabolism-related pathways, indicating that AS of metabolism-related genes is crucial for grain filling in wheat. Conclusions: Through transcriptome analysis, over ten thousand AS genes were identified and characterized in wheat cultivar Xiaoyan 6. Our study provides a comprehensive view of AS in the wheat cultivar Xiaoyan 6 and provides new insights into the complexity of AS in wheat. The data generated in this study provides a foundation for further studies of seed development in wheat.

scholarly journals Differential Alternative Splicing Genes and Isoform Regulation Networks of Rapeseed (Brassica napus L.) Infected with Sclerotinia sclerotiorum

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 784
Author(s):  
Jin-Qi Ma ◽  
Wen Xu ◽  
Fei Xu ◽  
Ai Lin ◽  
Wei Sun ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Brassica Napus ◽  
Sclerotinia Sclerotiorum ◽  
Defense Response ◽  
Gene Expression Regulation ◽  
Intron Retention ◽  
Transcriptional Response ◽  
Enrichment Analysis ◽  
Transcriptional Level ◽  
Brassica Napus L

Alternative splicing (AS) is a post-transcriptional level of gene expression regulation that increases transcriptome and proteome diversity. How the AS landscape of rapeseed (Brassica napus L.) changes in response to the fungal pathogen Sclerotinia sclerotiorum is unknown. Here, we analyzed 18 RNA-seq libraries of mock-inoculated and S. sclerotiorum-inoculated susceptible and tolerant B. napus plants. We found that infection increased AS, with intron retention being the main AS event. To determine the key genes functioning in the AS response, we performed a differential AS (DAS) analysis. We identified 79 DAS genes, including those encoding splicing factors, defense response proteins, crucial transcription factors and enzymes. We generated coexpression networks based on the splicing isoforms, rather than the genes, to explore the genes’ diverse functions. Using this weighted gene coexpression network analysis alongside a gene ontology enrichment analysis, we identified 11 modules putatively involved in the pathogen defense response. Within these regulatory modules, six DAS genes (ascorbate peroxidase 1, ser/arg-rich protein 34a, unknown function 1138, nitrilase 2, v-atpase f, and amino acid transporter 1) were considered to encode key isoforms involved in the defense response. This study provides insight into the post-transcriptional response of B. napus to S. sclerotiorum infection.

scholarly journals Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Target Genes ◽  
Intron Retention ◽  
Single Gene ◽  
Exon Skipping ◽  
Environmental Response ◽  
Biotic Stresses

Abstract Background Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing. Results We generate a massive resource for Arabidopsis thaliana, PastDB, comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets reveals that A. thaliana shows high levels of AS, similar to fruitflies, and that, compared to animals, disproportionately uses AS for stress responses. We identify core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that is tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, are overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion. Conclusions Non-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

scholarly journals The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 64
Author(s):  
Annamaria Tisi ◽  
Marco Feligioni ◽  
Maurizio Passacantando ◽  
Marco Ciancaglini ◽  
Rita Maccarone
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Blood Retinal Barrier ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Age Related ◽  
The Impact

The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch’s membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.

scholarly journals Developmental-Dependent Action of Microtubule Depolymerization on the Function and Structure of Synaptic Glycine Receptor Clusters in Spinal Neurons

2004 ◽  
Vol 91 (2) ◽  
pp. 1036-1049 ◽  
Author(s):  
Brigitte van Zundert ◽  
Francisco J. Alvarez ◽  
Juan Carlos Tapia ◽  
Hermes H. Yeh ◽  
Emilio Diaz ◽  
...  
Keyword(s):  
Average Length ◽  
Glycine Receptor ◽  
Colchicine Treatment ◽  
Morphological Properties ◽  
Microtubule Depolymerization ◽  
Spinal Neurons ◽  
Functional Changes ◽  
Microtubule Disruption ◽  
Immature Neurons ◽  
Mature Neurons

Microtubules have been proposed to interact with gephyrin/glycine receptors (GlyRs) in synaptic aggregates. However, the consequence of microtubule disruption on the structure of postsynaptic GlyR/gephyrin clusters is controversial and possible alterations in function are largely unknown. In this study, we have examined the physiological and morphological properties of GlyR/gephyrin clusters after colchicine treatment in cultured spinal neurons during development. In immature neurons (5-7 DIV), disruption of microtubules resulted in a 33 ± 4% decrease in the peak amplitude and a 72 ± 15% reduction in the frequency of spontaneous glycinergic miniature postsynaptic currents (mIPSCs) recorded in whole cell mode. However, similar colchicine treatments resulted in smaller effects on 10-12 DIV neurons and no effect on mature neurons (15-17 DIV). The decrease in glycinergic mIPSC amplitude and frequency reflects postsynaptic actions of colchicine, since postsynaptic stabilization of microtubules with GTP prevented both actions and similar reductions in mIPSC frequency were obtained by modifying the Cl- driving force to obtain parallel reductions in mIPSC amplitude. Confocal microscopy revealed that colchicine reduced the average length and immunofluorescence intensity of synaptic gephyrin/GlyR clusters in immature (approximately 30%) and intermediate (approximately 15%) neurons, but not in mature clusters. Thus the structural and functional changes of postsynaptic gephyrin/GlyR clusters after colchicine treatment were tightly correlated. Finally, RT-PCR, kinetic analysis and picrotoxin blockade of glycinergic mIPSCs indicated a reorganization of the postsynaptic region from containing both α2β and α1β GlyRs in immature neurons to only α1β GlyRs in mature neurons. Microtubule disruption preferentially affected postsynaptic sites containing α2β-containing synaptic receptors.

scholarly journals Developmental Origins of Kidney Disease: Why Oxidative Stress Matters?

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Chien-Ning Hsu ◽  
You-Lin Tain
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Current Knowledge ◽  
Future Research ◽  
Antioxidant Systems ◽  
Developmental Origins ◽  
Adult Onset ◽  
Functional Changes ◽  
Health And Disease ◽  
Developing Kidney

The “developmental origins of health and disease” theory indicates that many adult-onset diseases can originate in the earliest stages of life. The developing kidney has emerged as being particularly vulnerable to adverse in utero conditions leading to morphological and functional changes, namely renal programming. Emerging evidence indicates oxidative stress, an imbalance between reactive oxygen/nitrogen species (ROS/RNS) and antioxidant systems, plays a pathogenetic role in the developmental programming of kidney disease. Conversely, perinatal use of antioxidants has been implemented to reverse programming processes and prevent adult-onset diseases. We have termed this reprogramming. The focus of this review is twofold: (1) To summarize the current knowledge on oxidative stress implicated in renal programming and kidney disease of developmental origins; and (2) to provide an overview of reprogramming effects of perinatal antioxidant therapy on renal programming and how this may prevent adult-onset kidney disease. Although early-life oxidative stress is implicated in mediating renal programming and adverse offspring renal outcomes, and animal models provide promising results to allow perinatal antioxidants applied as potential reprogramming interventions, it is still awaiting clinical translation. This presents exciting new challenges and areas for future research.

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