title: Functional divergence and convergence between the transcript network and gene network in lung adenocarcinoma.
abstract: BACKGROUND
  Alternative RNA splicing is a critical regulatory mechanism during tumorigenesis. However, previous oncological studies mainly focused on the splicing of individual genes. Whether and how transcript isoforms are coordinated to affect cellular functions remain underexplored. Also of great interest is how the splicing regulome cooperates with the transcription regulome to facilitate tumorigenesis. The answers to these questions are of fundamental importance to cancer biology.
  
  
  RESULTS
  Here, we report a comparative study between the transcript-based network (TN) and the gene-based network (GN) derived from the transcriptomes of paired tumor-normal tissues from 77 lung adenocarcinoma patients. We demonstrate that the two networks differ significantly from each other in terms of patient clustering and the number and functions of network modules. Interestingly, the majority (89.5%) of multi-transcript genes have their transcript isoforms distributed in at least two TN modules, suggesting regulatory and functional divergences between transcript isoforms. Furthermore, TN and GN modules share onlŷ50%-60% of their biological functions. TN thus appears to constitute a regulatory layer separate from GN. Nevertheless, our results indicate that functional convergence and divergence both occur between TN and GN, implying complex interactions between the two regulatory layers. Finally, we report that the expression profiles of module members in both TN and GN shift dramatically yet concordantly during tumorigenesis. The mechanisms underlying this coordinated shifting remain unclear yet are worth further explorations.
  
  
  CONCLUSIONS
  We show that in lung adenocarcinoma, transcript isoforms per se are coordinately regulated to conduct biological functions not conveyed by the network of genes. However, the two networks may interact closely with each other by sharing the same or related biological functions. Unraveling the effects and mechanisms of such interactions will significantly advance our understanding of this deadly disease.
authors.affiliation: Department of Biological Science and Technology, National Chiao-Tung University, Hsinchu, Taiwan.
authors.forename: Min-Kung
authors.initials: MK
authors.lastname: Hsu
authors.affiliation: Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Pan
authors.affiliation: Department of Biological Science and Technology, National Chiao-Tung University, Hsinchu, Taiwan; Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; School of Dentistry, China Medical University, Taichung, Taiwan.
authors.forename: Feng-Chi
authors.initials: FC
authors.lastname: Chen
keywords: alternative splicing; gene network; lung adenocarcinoma; module; transcriptional regulation; transcriptome analysis
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