Uncovering the impacts of alternative splicing on the proteome with current omics techniques

Reixachs‐Solé, Marina; Eyras, Eduardo

doi:10.1002/wrna.1707

Cited by 41 publications

(25 citation statements)

References 222 publications

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“…Unfortunately, the acute H 2 O 2 exposure of this study does not lend itself to examining such changes, since changes in protein levels lag behind disruptions in RNA production and localization. In addition, many genes have multiple isoforms, which complicates most methods of quantifying protein level changes in response to changes in transcript localization in two ways: 1) each isoform can possess a varied localization pattern, and 2) it is largely unclear which isoforms of a given gene go on to produce proteins [ 41 ]. Indeed, future studies will require a longer stress-exposure timescale and a granular approach to determine whether and how the protein levels of particular genes are influenced by shifts in RNA localization.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress alters transcript localization of disease-causing genes in the retinal pigment epithelium

Kaczynski

Farkas

2021

Preprint

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Nuclear retention is a mechanism whereby RNA transcripts are held in the nucleus to maintain a proper nuclear-to-cytoplasmic balance or as a stockpile for use in responding to stimuli. Many mechanisms are employed to determine whether transcripts are retained or exported to the cytoplasm, though the extent to which tissue- or cell-type, stressors, or disease pathogenesis affect this process remains unclear. As the most biochemically active tissue in the body, the retina must mitigate endogenous and exogenous stressors to maintain cell health and tissue function. Oxidative stress, believed to contribute to the pathogenesis, or progression, of age-related macular degeneration (AMD) and inherited retinal dystrophies (IRDs), is produced both internally from biochemical processes, as well as externally from environmental insult. To evaluate the effect of oxidative stress on transcript localization in the retinal pigment epithelium (RPE), we performed poly-A RNA sequencing on nuclear and cytoplasmic fractions from induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells exposed to hydrogen peroxide, as well as untreated controls. Under normal conditions, the number of mRNA transcripts retained in the nucleus exceeded that found in studies of other tissues. Further, the nuclear-to-cytoplasmic ratio of transcripts is altered following oxidative stress, as is the retention of genes associated with AMD, IRDs, and those important for RPE physiology. These results provide a retention catalog of all expressed mRNA in iPSC-RPE under normal conditions and after exposure to hydrogen peroxide, offering insight into one of the potential roles oxidative stress plays in the progression of visual disorders.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress alters transcript localization of disease-causing genes in the retinal pigment epithelium

Kaczynski

Farkas

2021

Preprint

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“…Pre-mRNA, which has introns removed and exons joined at different combinations, generates new alternative transcript isoforms. Thus, different transcript isoforms produced from a single gene lead to the production of several protein variants, which impacts gene function through various mechanisms [ 59 ]. Alternative splicing not only provides insights into fundamental gene expression, but can also be harnessed as a strategy for therapeutic interventions [ 58 ].…”

Section: Alternative Splicing Variants: Psoriasis Isoformsmentioning

confidence: 99%

Transcriptional Basis of Psoriasis from Large Scale Gene Expression Studies: The Importance of Moving towards a Precision Medicine Approach

Krishnan

Kõks

2022

IJMS

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Transcriptome profiling techniques, such as microarrays and RNA sequencing (RNA-seq), are valuable tools for deciphering the regulatory network underlying psoriasis and have revealed large number of differentially expressed genes in lesional and non-lesional skin. Such approaches provide a more precise measurement of transcript levels and their isoforms than any other methods. Large cohort transcriptomic analyses have greatly improved our understanding of the physiological and molecular mechanisms underlying disease pathogenesis and progression. Here, we mostly review the findings of some important large scale psoriatic transcriptomic studies, and the benefits of such studies in elucidating potential therapeutic targets and biomarkers for psoriasis treatment. We also emphasised the importance of looking into the alternatively spliced RNA isoforms/transcripts in psoriasis, rather than focussing only on the gene-level annotation. The neutrophil and blood transcriptome signature in psoriasis is also briefly reviewed, as it provides the immune status information of patients and is a less invasive platform. The application of precision medicine in current management of psoriasis, by combining transcriptomic data, improves the clinical response outcome in individual patients. Drugs tailored to individual patient’s genetic profile will greatly improve patient outcome and cost savings for the healthcare system.

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“…Alternative splicing holds a central role in cellular metabolism and is considered a hub for cell differentiation and tissue development through the diversification of both the proteome and transcriptome (Kaliatsi et al, 2020;Khan et al, 2021;Reixachs-Solé and Eyras, 2022). It occurs in most human genes, with an estimated percentage exceeding 90% (Xiao and Lee, 2010).…”

Section: Introductionmentioning

confidence: 99%

Aberrant splicing in human cancer: An RNA structural code point of view

Apostolidi

Stamatopoulou

2023

Front. Pharmacol.

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Alternative splicing represents an essential process that occurs widely in eukaryotes. In humans, most genes undergo alternative splicing to ensure transcriptome and proteome diversity reflecting their functional complexity. Over the last decade, aberrantly spliced transcripts due to mutations in cis- or trans-acting splicing regulators have been tightly associated with cancer development, largely drawing scientific attention. Although a plethora of single proteins, ribonucleoproteins, complexed RNAs, and short RNA sequences have emerged as nodal contributors to the splicing cascade, the role of RNA secondary structures in warranting splicing fidelity has been underestimated. Recent studies have leveraged the establishment of novel high-throughput methodologies and bioinformatic tools to shed light on an additional layer of splicing regulation in the context of RNA structural elements. This short review focuses on the most recent available data on splicing mechanism regulation on the basis of RNA secondary structure, emphasizing the importance of the complex RNA G-quadruplex structures (rG4s), and other specific RNA motifs identified as splicing silencers or enhancers. Moreover, it intends to provide knowledge on newly established techniques that allow the identification of RNA structural elements and highlight the potential to develop new RNA-oriented therapeutic strategies against cancer.

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Uncovering the impacts of alternative splicing on the proteome with current omics techniques

Cited by 41 publications

References 222 publications

Oxidative stress alters transcript localization of disease-causing genes in the retinal pigment epithelium

Oxidative stress alters transcript localization of disease-causing genes in the retinal pigment epithelium

Transcriptional Basis of Psoriasis from Large Scale Gene Expression Studies: The Importance of Moving towards a Precision Medicine Approach

Aberrant splicing in human cancer: An RNA structural code point of view

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