scholarly journals Two Proteins Essential for Apolipoprotein B mRNA Editing Are Expressed from a Single Gene through Alternative Splicing

2002 ◽  
Vol 277 (15) ◽  
pp. 12703-12709 ◽  
Author(s):  
Geoffrey S. C. Dance ◽  
Mark P. Sowden ◽  
Luca Cartegni ◽  
Ellen Cooper ◽  
Adrian R. Krainer ◽  
...  
2003 ◽  
Vol 369 (2) ◽  
pp. 255-262 ◽  
Author(s):  
Martin HERSBERGER ◽  
Susannah PATARROYO-WHITE ◽  
Xiaobing QIAN ◽  
Kay S. ARNOLD ◽  
Lucia ROHRER ◽  
...  

Apolipoprotein (apo) B mRNA editing is the deamination of C6666 to uridine, which results in translation of the apoB-48 protein instead of the genomically encoded apoB-100. ApoB-48-containing lipoproteins are cleared more rapidly from plasma and are less atherogenic than apoB-100-containing low-density lipoproteins (LDLs). In humans, the intestine predominantly produces apoB-48 whereas the liver secretes apoB-100 only. To evaluate a potential therapeutic use for liver-induced apoB mRNA editing in humans, we investigated the efficiency and safety of transgenic expression of apoB mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1) in the absence of endogenous editing in the mouse model. Here we show that regulatable tetO-mediated APOBEC-1 expression in the livers of gene-targeted mice lacking endogenous APOBEC-1 results in 30% apoB mRNA editing. In a time-course experiment, the expression of tetO-APOBEC-1 mRNA was suppressed within 2 days after mice were fed doxycycline and apoB mRNA editing and apoB-48 formation were suppressed within 4 days. However, tetO-APOBEC-1 expression resulted in regulatable aberrant hyperediting of several cytidines downstream of C6666 in apoB mRNA and in novel APOBEC-1 target 1 (NAT1) mRNA. Several of the cytidines in apoB mRNA were hyperedited to a level similar to that of C6666, although editing at C6666 was lower than that in wild-type mice. These results demonstrate that even moderate APOBEC-1 expression can lead to hyperediting, limiting the single-gene approach for gene therapy with APOBEC-1.


2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt

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.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia

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.


1999 ◽  
Vol 40 (4) ◽  
pp. 623-635 ◽  
Author(s):  
Ba-Bie Teng ◽  
Scott Ochsner ◽  
Qian Zhang ◽  
Kizhake V. Soman ◽  
Paul P. Lau ◽  
...  

1990 ◽  
Vol 265 (36) ◽  
pp. 22446-22452 ◽  
Author(s):  
K Boström ◽  
Z Garcia ◽  
K S Poksay ◽  
D F Johnson ◽  
A J Lusis ◽  
...  

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Dunhui Li ◽  
Craig Stewart McIntosh ◽  
Frank Louis Mastaglia ◽  
Steve Donald Wilton ◽  
May Thandar Aung-Htut

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.


2018 ◽  
pp. 297-317
Author(s):  
Nicholas O. Davidson

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