An extensive program of periodic alternative splicing linked to cell cycle progression

• Published in: eLife Vol. 5
• Main Authors: Dominguez, Daniel, Tsai, Yi-Hsuan, Weatheritt, Robert, Wang, Yang, Blencowe, Benjamin J, Wang, Zefeng
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 25.03.2016; eLife Sciences Publications, Ltd
• Subjects: Alternative Splicing; Biology; Cancer; cancer genomic; Cell Biology; Cell Cycle; Cell Line, Tumor; Epithelial Cells - physiology; Gene Expression; Gene Expression Profiling; Gene Knockout Techniques; Genes; Genomics and Evolutionary Biology; Humans; Kinases; Overexpression; Phosphorylation; Pipelines; Post-translation; Protein interaction; Protein kinase; Protein kinase C; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; Transcription; cell biology; evolutionary biology; alternative splicing; cell cycle; genomics; human; cancer genomic
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.10288

Progression through the mitotic cell cycle requires periodic regulation of gene function at the levels of transcription, translation, protein-protein interactions, post-translational modification and degradation. However, the role of alternative splicing (AS) in the temporal control of cell cycle is not well understood. By sequencing the human transcriptome through two continuous cell cycles, we identify ~1300 genes with cell cycle-dependent AS changes. These genes are significantly enriched in functions linked to cell cycle control, yet they do not significantly overlap genes subject to periodic changes in steady-state transcript levels. Many of the periodically spliced genes are controlled by the SR protein kinase CLK1, whose level undergoes cell cycle-dependent fluctuations via an auto-inhibitory circuit. Disruption of CLK1 causes pleiotropic cell cycle defects and loss of proliferation, whereas CLK1 over-expression is associated with various cancers. These results thus reveal a large program of CLK1-regulated periodic AS intimately associated with cell cycle control. Mitosis is a key step in the normal life cycle of a cell, during which one cell divides into two new cells. As a cell progresses through the cell cycle, it must carefully regulate its gene activity to switch particular genes on or off at specific moments. When a gene is activated its sequence is first copied into a temporary molecule called a transcript. These transcripts are then edited to form templates to build proteins. One way that a transcript can be edited is via a process called alternative splicing, in which different pieces of the transcript are cut and pasted together to form different versions of the final template. This allows different instructions to be obtained from a single gene, introducing an added layer of biological complexity. However, the role of alternative splicing in the timing of key events of the cell life cycle is not well understood. Dominguez et al. have now looked for the genes that undergo alternative splicing during the cell cycle. The sequences of gene transcripts produced within human cells were collected while the cells went through two rounds of division. This approach revealed that around 1,300 genes are spliced in different ways at different stages of each cell cycle. Many of these genes were known to play roles in controlling the cell’s life cycle, but few of the genes showed large changes in the amount of total transcript that is generated over time. Dominguez et al. also showed that an enzyme called CLK1 influences about half of the 1,300 periodically spliced genes during the cell cycle. The production of CLK1 is itself carefully controlled throughout the cell cycle, and the enzyme’s activity prevents its own overproduction. Further experiments showed that blocking CLK1’s activity while a cell is replicating its DNA halts the cell cycle, but blocking this enzyme’s activity after the cell had replicated its DNA did not. Given this pivotal role in the cell cycle, Dominguez et al. also examined the role of CLK1 in cancer cells and found that high levels of CLK1 in tumours were linked to lower survival rates. These findings indicate that CLK1 warrants further investigation, particularly in relation to its role in cancer.