Alternative splicing

Alternative splicing, or differential splicing, is a regulated process during gene expression that results in a single gene coding for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene.

Consequently, the proteins translated will contain differences in their amino acid sequence and, often, in their biological functions.

Notably, alternative splicing allows the human genome to direct the synthesis of many more proteins than would be expected from its 20,000 protein-coding genes.

Alternative spicing (AS) plays a key role in numerous pathologies, including cancer.

Larionova et al. found that the compositions of ribosomes of Glioblastoma cells in the tumour core and edge differ due to alternative RNA splicing. The acidic pH in the core switches before messenger RNA splicing of the ribosomal gene RPL22L1 towards the RPL22L1b isoform. This allows cells to survive acidosis, increases stemness and correlates with worse patient outcome. Mechanistically, RPL22L1b promotes RNA splicing by interacting with lncMALAT1 in the nucleus and inducing its degradation. Contrarily, in the tumour edge region, RPL22L1a interacts with ribosomes in the cytoplasm and upregulates the translation of multiple messenger RNAs including TP53. We found that the RPL22L1 isoform switch is regulated by SRSF4 and identified a compound that inhibits this process and decreases tumour growth. These findings demonstrate how distinct GBM cell populations arise during tumour growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy 1)

Alternative splicing (AS) events can affect cell function by splicing precursor mRNA. Therefore, a prognostic model for LGG based on AS events are important to establish.

RNA sequencing, clinical, and AS event data of 510 LGG patients from the TCGA database were downloaded. Univariate Cox regression analysis was used to screen out prognostic-related AS events and LASSO regression and multivariate Cox regression were used to establish prognostic risk scores for patients in the training set (n = 340). After validation, a nomogram model was established based on the AS signature and clinical information, which was able to predict 1-, 3-, and 5-year survival rates. Finally, considering the regulatory effect of splicing factors (SFs) on AS events, an AS-SF regulatory network was analyzed.

Results: The most common AS event was exon skipping and the least was mutually exclusive exons. All the seven AS events were related to the prognosis of LGG patients, regardless of whether they were separated or considered as a whole event (integrated AS event), and the integrated AS event had the most significant correlation. After further inclusion of clinical indicators, eight factors were screened out: age, new event, KPS, WHO grade, treatment, integrated AS signature, IDH1 and TP53 mutation status, and a nomogram model was established. The study also constructed an AS-SF regulatory network.

Conclusion: The AS events and clinical factors that can predict the prognosis of LGG patients were screened, and a prognostic prediction model was established. The results of this study can play an important role in clinical work to better evaluate the prognosis of patients and impact treatment options 2).

The objective of a study was to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation.

We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma.

BAF45d is part of the switch/sucrose non-fermentable (SWI/SNF) complex and plays a key role in the development of the CNS. The BAF45d/6A-isoform is present in 85% of over 200 glioma samples that have been analyzed, and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine-tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription.

Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease 3).

Larionova TD, Bastola S, Aksinina TE, Anufrieva KS, Wang J, Shender VO, Andreev DE, Kovalenko TF, Arapidi GP, Shnaider PV, Kazakova AN, Latyshev YA, Tatarskiy VV, Shtil AA, Moreau P, Giraud F, Li C, Wang Y, Rubtsova MP, Dontsova OA, Condro M, Ellingson BM, Shakhparonov MI, Kornblum HI, Nakano I, Pavlyukov MS. Alternative RNA splicing modulates ribosomal composition and determines the spatial phenotype of glioblastoma cells. Nat Cell Biol. 2022 Oct 3. doi: 10.1038/s41556-022-00994-w. Epub ahead of print. PMID: 36192632.
Wang Y, Wang Z, Zhao B, Chen W, Wang Y, Ma W. Development of a nomogram for prognostic prediction of lower-grade glioma based on alternative splicing signatures. Cancer Med. 2020 Oct 13. doi: 10.1002/cam4.3530. Epub ahead of print. PMID: 33047900.
Aldave G, Gonzalez-Huarriz M, Rubio A, Romero JP, Ravi D, Miñana B, Cuadrado-Tejedor M, García-Osta A, Verhaak R, Xipell E, Martinez-Vélez N, Acanda de la Rocha A, Puigdelloses M, García-Moure M, Marigil M, Gállego Pérez-Larraya J, Marín-Bejar O, Huarte M, Carro MS, Ferrarese R, Belda-Iniesta C, Ayuso A, Prat-Acín R, Pastor F, Díez-Valle R, Tejada S, Alonso MM. The aberrant splicing of BAF45d links splicing regulation and transcription in glioblastoma. Neuro Oncol. 2018 Jan 24. doi: 10.1093/neuonc/noy007. [Epub ahead of print] PubMed PMID: 29373718.
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