Microexon alternative splicing of small <scp>GTPase</scp> regulators: Implication in central nervous system diseases

Lee, Jeesan; Lamarche-Vane, Nathalie; Richard, Stéphane

doi:10.1002/wrna.1678

Cited by 11 publications

(8 citation statements)

References 129 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our software, we integrated the eukaryotic linear motif (ELM) database and the NEASE method to specifically address the functional consequences at the exon-level. Additionally, previous work has found that spliced exons less than 250 nt are significantly conserved in terms of length and sequence across vertebrate species [12, 19, 43, 44]. We clustered differential AS genes and exons into three groups based on the length of the corresponding spliced exons: ≤ 51 nt, 52-250 nt, and ≥ 251 nt.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that micro-exons exhibit tissue-specific expression patterns and play important roles in cell differentiation, cell migration, neuronal and glial functions [16][17][18]. Mis-regulated micro-exons appear to contribute to the development of neurological disorders and cancer [19]. In our ASTK pipeline, we provide the option to cluster AS genes according to spliced exon lengths before running downstream analysis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ASTK: a machine learning-based integrative software for alternative splicing analysis

Huang

Guo

et al. 2023

Preprint

View full text Add to dashboard Cite

Alternative splicing (AS) is pervasive and a key regulatory mechanism leading to diverse protein isoforms with distinct functions. Next-generation sequencing has enabled genome-wide studies of AS. However, AS analysis of massive amount of transcriptomic data generated by RNAseq is challenging due to the limited functions of current software packages, calling for a comprehensive and flexible pipeline. Here, we present ASTK, a software package combing diverse tools to systematically analyze AS events: including clustering AS genes based on spliced exon lengths, sequence feature extraction, functional enrichment analysis for spliced genes and spliced exons respectively, identifying binding motifs of RNA-binding proteins (RBPs) surrounding splice sites, and characterizing splicing-associated histone marks and chromatin states. ASTK was tested using experimental datasets to show its effectiveness and reliability. In our test cases, we grouped differential AS genes/spliced exons into three classes based on the length of spliced exons, which tend to be enriched into discrete functions. Furthermore, we identified several sequence features and epigenetic marks associated with the inclusion level of spliced exons. Therefore, ASTK will facilitate the functional characterization of AS events and improve our understanding of splicing regulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ASTK: a machine learning-based integrative software for alternative splicing analysis

Huang

Guo

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Through AS, hundreds of thousands of RNA isoforms with distinct structural properties, localization patterns, and translation efficiencies can be expressed as protein isoforms with diverse functions [ 9 ]. Moreover, the misregulation of AS has been linked to various diseases, such as central nervous system diseases [ 10 ], heart diseases [ 11 ], carcinoma [ 12 ], immune diseases [ 13 ], and metabolic diseases [ 14 ]. Preexisting studies have also revealed the alternative splicing of VEGF [ 15 ], TUBD1 [ 16 ] in DR.…”

Section: Introductionmentioning

confidence: 99%

“…RNA-binding proteins (RBPs) are vital regulators of an mRNA life cycle, including their transcription, splicing export, and transport to degradation, deadenylation, storage, silencing, and mRNA translation (protein synthesis) [ 17 , 18 ]. Along with the spliceosome complex, RBPs have a major role in creating cell-type-specific regulation of alternative splicing [ 10 , 19 , 20 ]. Previous researchers have revealed the regulatory role of zinc finger RNA-binding protein [ 21 ] and the ELAVL1 (or human antigen R (HuR)) RNA-binding protein [ 22 ] in DR.…”

Section: Introductionmentioning

confidence: 99%

RNA-Binding Proteins and Alternative Splicing Genes Are Coregulated in Human Retinal Endothelial Cells Treated with High Glucose

Zhao

Kong

Wang

et al. 2022

Journal of Diabetes Research

View full text Add to dashboard Cite

To explore the relevant RNA-binding proteins (RBPs) and alternative splicing events (ASEs) in diabetic retinopathy (DR). We devised a comprehensive work to integrate analyses of the differentially expressed genes, including differential RBPs, and variable splicing characteristics related to DR in human retinal endothelial cells induced by low glucose and high glucose in dataset GSE117238. A total of 2320 differentially expressed genes (DEGs) were identified, including 1228 upregulated genes and 1092 downregulated genes. Further analysis screened out 232 RBP genes, and 42 AS genes overlapped DEGs. We selected high expression and consistency six RBP genes (FUS, HNRNPA2B1, CANX, EIF1, CALR, and POLR2A) for coexpression analysis. Through analysis, we found eight RASGs (MDM2, GOLGA2P7, NFE2L1, KDM4A, FAM111A, CIRBP, IDH1, and MCM7) that could be regulated by RBP. The coexpression network was conducted to further elucidate the regulatory and interaction relationship between RBPs and AS. Apoptotic progress, protein phosphorylation, and NF-kappaB cascade revealed by the functional enrichment analysis of RASGs regulated by RBPs were closely related to diabetic retinopathy. Furthermore, the expression of differentially expressed RBPs was validated by qRT-PCR in mouse retinal microvascular endothelial cells and retinas from the streptozotocin mouse model. The results showed that Fus, Hnrnpa2b1, Canx, Calr, and Polr2a were remarkedly difference in high-glucose-treated retinal microvascular endothelial cells and Fus, Hnrnpa2b1, Canx, and Calr were remarkedly difference in retinas from streptozotocin-induced diabetic mice compared to control. The regulatory network between identified RBPs and RASGs suggests the presence of several signaling pathways possibly involved in the pathogenesis of DR. The verified RBPs should be further addressed by future studies investigating associations between RBPs and the downstream of AS, as they could serve as potential biomarkers and targets for DR.

show abstract

“…Small GTPases contain a diverse set of exons with propensity for alternative splicing that can impact biology, including neurodevelopmental disorders and cancer ( Lee et al, 2022 ). Within cancer, splicing changes in small GTPases have been noted for genes including NRAS , KRAS , HRAS , and RAC1 ( Rásó, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

Das

Sherry

Vaughan

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The small GTPase family is well-studied in cancer and cellular physiology. With 162 annotated human genes, the family has a broad expression throughout cells of the body. Members of the family have multiple exons that require splicing. Yet, the role of splicing within the family has been underexplored. We have studied the splicing dynamics of small GTPases throughout 41,671 samples by integrating Nanopore and Illumina sequencing techniques. Within this work, we have made several discoveries. 1). Using the GTEx long read data of 92 samples, each small GTPase gene averages two transcripts, with 83 genes (51%) expressing two or more isoforms. 2). Cross-tissue analysis of GTEx from 17,382 samples shows 41 genes (25%) expressing two or more protein-coding isoforms. These include protein-changing transcripts in genes such as RHOA, RAB37, RAB40C, RAB4B, RAB5C, RHOC, RAB1A, RAN, RHEB, RAC1, and KRAS. 3). The isolation and library technique of the RNAseq influences the abundance of non-sense-mediated decay and retained intron transcripts of small GTPases, which are observed more often in genes than appreciated. 4). Analysis of 16,243 samples of “Blood PAXgene” identified seven genes (3.7%; RHOA, RAB40C, RAB4B, RAB37, RAB5B, RAB5C, RHOC) with two or more transcripts expressed as the major isoform (75% of the total gene), suggesting a role of genetics in altering splicing. 5). Rare (ARL6, RAB23, ARL13B, HRAS, NRAS) and common variants (GEM, RHOC, MRAS, RAB5B, RERG, ARL16) can influence splicing and have an impact on phenotypes and diseases. 6). Multiple genes (RAB9A, RAP2C, ARL4A, RAB3A, RAB26, RAB3C, RASL10A, RAB40B, and HRAS) have sex differences in transcript expression. 7). Several exons are included or excluded for small GTPase genes (RASEF, KRAS, RAC1, RHEB, ARL4A, RHOA, RAB30, RHOBTB1, ARL16, RAP1A) in one or more forms of cancer. 8). Ten transcripts are altered in hypoxia (SAR1B, IFT27, ARL14, RAB11A, RAB10, RAB38, RAN, RIT1, RAB9A) with RHOA identified to have a transient 3′UTR RNA base editing at a conserved site found in all of its transcripts. Overall, we show a remarkable and dynamic role of splicing within the small GTPase family that requires future explorations.

show abstract

Microexon alternative splicing of small GTPase regulators: Implication in central nervous system diseases

Cited by 11 publications

References 129 publications

ASTK: a machine learning-based integrative software for alternative splicing analysis

ASTK: a machine learning-based integrative software for alternative splicing analysis

RNA-Binding Proteins and Alternative Splicing Genes Are Coregulated in Human Retinal Endothelial Cells Treated with High Glucose

The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

Contact Info

Product

Resources

About