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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 from alternatively spliced mRNAs 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. 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 1).

1)
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.
alternative_splicing.txt · Last modified: 2018/02/02 17:35 by administrador