Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines

Abstract

Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes TRAF1, TNFRSF12A and NFKB2. Our results point to a role of temporal alternative splicing in isoform production, which may alter the outcome of the TNF pathway and impact on tumorigenesis.

Construction of prognostic predictor by comprehensive analyzing alternative splicing events for colon adenocarcinoma

“…Abnormal AS has been identified as a molecular trigger for cancer [ 14 ]. Various studies have shown that the transcript variants of a gene may have opposing roles, and AS is known to be a key factor in cancer progression, including proliferation, apoptosis, invasion, angiogenesis, and metabolism [ 15 , 16 ]. For example, an EGFR splice variant, lacks exon 4 (de4 EGFR), was found to constitutively activate downstream pathways to promote cancer cell proliferation and metastasis in glioma, prostate cancer, and ovarian cancer tissues [ 17 ].…”

Construction of prognostic predictor by comprehensive analyzing alternative splicing events for Colon adenocarcinoma

“…Abnormal AS has been identi ed as a molecular trigger for cancer [14]. Various studies have shown that the transcript variants of a gene may have opposing roles, and AS is known to be a key factor in cancer progression, including proliferation, apoptosis, invasion, angiogenesis, and metabolism [15,16]. For example, an EGFR splice variant, lacksexon 4 (de4 EGFR), was found to constitutively activate downstream pathways to promote cancer cell proliferation and metastasis in glioma, prostate cancer, and ovarian cancer tissues [17].…”

An Optimal Time for Treatment—Predicting Circadian Time by Machine Learning and Mathematical Modelling

“…The circadian transcriptome is defined as the set of expressed genes, which show a rhythmic behavior in their mRNA expression levels with a periodicity of ~24 h. Early studies using microarrays revealed the existence of rhythmic gene expression profiles in various organisms from fruit flies to humans [ 129 , 130 , 131 , 132 , 133 ]. With the development of next generation sequencing (NGS) platforms, RNA-seq became one of the most commonly used high-throughput platforms for the generation of time-course expression data [ 29 , 30 ]. Other NGS platforms widely used in the field include chromatin immune precipitation DNA-sequencing (CHIP-seq) [ 134 , 135 ] for studying the transcriptional and chromatin regulation of clock-controlled rhythms and regulation of cycling mRNAs, which revealed links to biological processes (e.g., metabolism) [ 136 ].…”

“…The interplay between these two transcription/translation feedback loops orchestrates the circadian oscillatory mechanism in cells ( Figure 1 A). This intricate time keeping system plays a significant role in regulating various molecular and cellular functions from RNA processing to immune pathways, it controls several steps in metabolic pathways and governs the expression patterns of numerous cell cycle proteins [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Subsequently, disruption in circadian processes may not only favor cancer progression but also result in various other pathologies [ 33 , 34 , 35 , 36 ].…”