TF–RBP–AS Triplet Analysis Reveals the Mechanisms of Aberrant Alternative Splicing Events in Kidney Cancer: Implications for Their Possible Clinical Use as Prognostic and Therapeutic Biomarkers

Abstract

Aberrant alternative splicing (AS) is increasingly linked to cancer; however, how AS contributes to cancer development still remains largely unknown. AS events (ASEs) are largely regulated by RNA-binding proteins (RBPs) whose ability can be modulated by a variety of genetic and epigenetic mechanisms. In this study, we used a computational framework to investigate the roles of transcription factors (TFs) on regulating RBP-AS interactions. A total of 6519 TF–RBP–AS triplets were identified, including 290 TFs, 175 RBPs, and 16 ASEs from TCGA–KIRC RNA sequencing data. TF function categories were defined according to correlation changes between RBP expression and their targeted ASEs. The results suggested that most TFs affected multiple targets, and six different classes of TF-mediated transcriptional dysregulations were identified. Then, regulatory networks were constructed for TF–RBP–AS triplets. Further pathway-enrichment analysis showed that these TFs and RBPs involved in triplets were enriched in a variety of pathways that were associated with cancer development and progression. Survival analysis showed that some triplets were highly associated with survival rates. These findings demonstrated that the integration of TFs into alternative splicing regulatory networks can help us in understanding the roles of alternative splicing in cancer.

Differential alternative splicing genes and isoform co-expression networks of Brassica napus under multiple abiotic stresses

“…These results revealed that transcription factors cannot only activate or inhibit gene transcription, but also undergo constitutive and inducible AS under abiotic stresses. Interestingly, we found that TFs tended to co-express with RBPs in the modules related to various abiotic stresses, and both of them were hub genes/isoforms, which was consistent with previous reports ( He and Hu, 2021 ).…”

Development and implementation of a prognostic model for clear cell renal cell carcinoma based on heterogeneous TLR4 expression

“…First, we performed a differential analysis on samples with varying TLR4 expression in the TCGA-KIRC cohort to identify differentially expressed genes. This approach aligns with recent research methodologies, wherein similar techniques have been employed to study other types of cancers [ 37 ]. Subsequently, we integrated genes from the renal cell carcinoma pathway in the KEGG database and identified TRGs through intersection analysis.…”

Identification of alternative splicing associated with clinical features: from pan-cancers to genitourinary tumors

“…The expression of splicing factors was also reported to be regulated by DNA methylation and histone modification ( 60 – 62 ). Furthermore, a transcription factors-RBPs-AS triplet analysis was used to interpret aberrant ASEs in cancer ( 63 ). Our results identified RBPs including PCBP2 and SNRNP70 responsible for differential ASEs upregulated in BLCA with high-level neoplasm grade.…”