Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay

García-Moreno, Juan F.; Romão, Luı́sa

doi:10.3390/ijms21249424

Cited by 53 publications

(54 citation statements)

References 159 publications

(217 reference statements)

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“…We found poison exons expressed predominantly in Lin-neg cells. This finding underscores the role of alternatively spliced poison exons as a potential regulator of gene expression during differentiation of hematopoietic stem cells as described by others (García-Moreno and Romão 2020; Lareau et al 2007a; Leclair et al 2020; Jacob and Smith 2017). Overall, our single-cell analysis of bone marrow populations revealed that lineage-negative cells express more diverse splice variants with higher content of novel isoforms.…”

Section: Discussionsupporting

confidence: 81%

“…Of particular interest, SMG1 is involved in nonsense-mediated mRNA decay (NMD, (Powers et al 2020)) and we have observed an overall increase of intron retention in Lin-neg cells (Figure 3B). This observation led us to investigate the expression of "poison exons" of SRSF genes, defined as ultraconserved regions containing noncoding exons, that, cause NMD when spliced-in (Lareau et al 2007b;Leclair et al 2020;García-Moreno and Romão 2020;Jacob and Smith 2017). Indeed, we found such sequences for SRSF2, 5, 6 and 7 when we entered the coordinates published in (Leclair et al 2020).…”

Section: Resultsmentioning

confidence: 96%

“…3B). This observation led us to investigate the expression of “poison exons” of SRSF genes, defined as ultra-conserved regions containing noncoding exons, that, cause NMD when spliced-in (Lareau et al 2007b; Leclair et al 2020; García-Moreno and Romão 2020; Jacob and Smith 2017). Indeed, we found such sequences for SRSF2, 5, 6 and 7 when we entered the coordinates published in (Leclair et al 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Intron retention may cause the emergence of a premature termination codon (PTC), which in turn can lead to nonsense-mediated decay (NMD) of mRNA. But NMD is not only an RNA surveillance mechanism in order to degrade mRNAs with nonsense mutations but also serves in an essential regulatory role in post-transcriptional gene expression control in vertebrates (Yi et al 2020; García-Moreno and Romão 2020; Wong et al 2018; Lykke-Andersen and Jensen 2015). Finally, previous research has shown that SR proteins are auto-regulated by alternative splicing coupled to nonsense-mediated decay (AS-NMD).…”

Section: Discussionmentioning

confidence: 99%

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Full-length, single-cell RNA-sequencing of human bone marrow subpopulations reveals hidden complexity

Schmidt

Mays²,

Barefoot

et al. 2021

Preprint

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Bone marrow progenitor cell differentiation has frequently been used as a model for studying cellular plasticity and cell-fate decisions. Recent analysis at the level of single-cells has expanded knowledge of the transcriptional landscape of human hematopoietic cell lineages. Using single-molecule real-time (SMRT) full-length RNA sequencing, we have previously shown that human bone marrow lineage-negative (Lin-neg) cell populations contain a surprisingly diverse set of mRNA isoforms. Here, we report from single cell, full-length RNA sequencing that this diversity is also reflected at the single-cell level. From fresh human bone marrow unselected and lineage-negative progenitor cells were isolated by droplet-based single-cell selection (10xGenomics). The single cell-derived mRNAs were analyzed by full-length SMRT and short-read sequencing. In both samples we detected an average of 8000 different genes using short-read sequencing. Differential expression analysis arranged the single-cells of the total bone marrow into only four clusters whereas the Lin-neg population was much more diverse with nine clusters. mRNA isoform analysis of the single-cell populations using full-length sequencing revealed that Lin-neg cells contain on average 24% more novel splice variants than the total bone marrow cells. Interestingly, among the most frequent genes expressing novel isoforms were members of the spliceosome, e.g. HNRNPs, DEAD box helicases and SRSFs. Mapping the isoforms from all genes to the cell type clusters revealed that total bone marrow cells express novel isoforms only in a small subset of clusters. On the other hand, lineage-negative progenitor cells expressing novel isoforms were present in nearly all subpopulations. In conclusion, on a single-cell level lineage-negative cells express a higher diversity of genes and more alternatively spliced novel isoforms suggesting that cells in this subpopulation are poised for different fates.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Full-length, single-cell RNA-sequencing of human bone marrow subpopulations reveals hidden complexity

Schmidt

Mays²,

Barefoot

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In normal cells, not all of these aberrant RNA variants have the possibility to produce protein isoforms. It was proposed that about 30% of alternatively spliced transcripts in human cells contain premature termination codons that will result in the degradation of the RNA through nonsense-mediated decay [ 134 ]. Moreover, great numbers of these RNA variants are noncoding RNA.…”

Section: Neoantigens Produced By Alternative Splicingmentioning

confidence: 99%

Alternative Splicing of Pre-mRNA in the Control of Immune Activity

Huang

2021

Genes

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The human immune response is a complex process that responds to numerous exogenous antigens in preventing infection by microorganisms, as well as to endogenous components in the surveillance of tumors and autoimmune diseases, and a great number of molecules are necessary to carry the functional complexity of immune activity. Alternative splicing of pre-mRNA plays an important role in immune cell development and regulation of immune activity through yielding diverse transcriptional isoforms to supplement the function of limited genes associated with the immune reaction. In addition, multiple factors have been identified as being involved in the control of alternative splicing at the cis, trans, or co-transcriptional level, and the aberrant splicing of RNA leads to the abnormal modulation of immune activity in infections, immune diseases, and tumors. In this review, we summarize the recent discoveries on the generation of immune-associated alternative splice variants, clinical disorders, and possible regulatory mechanisms. We also discuss the immune responses to the neoantigens produced by alternative splicing, and finally, we issue some alternative splicing and immunity correlated questions based on our knowledge.

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RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy

Shen,

Shentu,

Zhong

et al. 2024

Clinical & Translational Med

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BackgroundAlternative splicing of pre‐mRNA is a fundamental regulatory process in multicellular eukaryotes, significantly contributing to the diversification of the human proteome. RNA‐binding fox‐1 homologue 2 (RBFOX2), a member of the evolutionarily conserved RBFOX family, has emerged as a critical splicing regulator, playing a pivotal role in the alternative splicing of pre‐mRNA. This review provides a comprehensive analysis of RBFOX2, elucidating its splicing activity through direct and indirect binding mechanisms. RBFOX2 exerts substantial influence over the alternative splicing of numerous transcripts, thereby shaping essential cellular processes such as differentiation and development.Main body of the abstractDysregulation of RBFOX2‐mediated alternative splicing has been closely linked to a spectrum of cardiovascular diseases and malignant tumours, underscoring its potential as a therapeutic target. Despite significant progress, current research faces notable challenges. The complete structural characterisation of RBFOX2 remains elusive, limiting in‐depth exploration beyond its RNA‐recognition motif. Furthermore, the scarcity of studies focusing on RBFOX2‐targeting drugs poses a hindrance to translating research findings into clinical applications.ConclusionThis review critically assesses the existing body of knowledge on RBFOX2, highlighting research gaps and limitations. By delineating these areas, this analysis not only serves as a foundational reference for future studies but also provides strategic insights for bridging these gaps. Addressing these challenges will be instrumental in unlocking the full therapeutic potential of RBFOX2, paving the way for innovative and effective treatments in various diseases.

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Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay

Cited by 53 publications

References 159 publications

Full-length, single-cell RNA-sequencing of human bone marrow subpopulations reveals hidden complexity

Full-length, single-cell RNA-sequencing of human bone marrow subpopulations reveals hidden complexity

Alternative Splicing of Pre-mRNA in the Control of Immune Activity

RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy

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