Roles of alternative splicing in modulating transcriptional regulation

Jin Li, Yang Wang, Xi Rao, Yue Wang, Weixing Feng, Hong Liang, Yunlong Liu

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: The ability of a transcription factor to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms. Alternative splicing can modulate gene function by adding or removing certain protein domains, and therefore affect the activity of protein. Reverse engineering of gene regulatory networks using gene expression profiles has proven valuable in dissecting the logical relationships among multiple proteins during the transcriptional regulation. However, it is unclear whether alternative splicing of certain proteins affects the activity of other transcription factors. Results: In order to investigate the roles of alternative splicing during transcriptional regulation, we constructed a statistical model to infer whether the alternative splicing events of modulator proteins can affect the ability of key transcription factors in regulating the expression levels of their transcriptional targets. We tested our strategy in KIRC (Kidney Renal Clear Cell Carcinoma) using the RNA-seq data downloaded from TCGA (the Cancer Genomic Atlas). We identified 828of modulation relationships between the splicing levels of modulator proteins and activity levels of transcription factors. For instance, we found that the activity levels of GR (glucocorticoid receptor) protein, a key transcription factor in kidney, can be influenced by the splicing status of multiple proteins, including TP53, MDM2 (mouse double minute 2 homolog), RBM14 (RNA-binding protein 14) and SLK (STE20 like kinase). The influenced GR-targets are enriched by key cancer-related pathways, including p53 signaling pathway, TR/RXR activation, CAR/RXR activation, G1/S checkpoint regulation pathway, and G2/M DNA damage checkpoint regulation pathway. Conclusions: Our analysis suggests, for the first time, that exon inclusion levels of certain regulatory proteins can affect the activities of many transcription factors. Such analysis can potentially unravel a novel mechanism of how splicing variation influences the cellular function and provide important insights for how dysregulation of splicing outcome can lead to various diseases.

Original languageEnglish (US)
Article number89
JournalBMC Systems Biology
Volume11
DOIs
StatePublished - Oct 3 2017

Fingerprint

Alternative Splicing
Transcriptional Regulation
Transcription factors
Transcription Factors
Proteins
Protein
Transcription Factor
Glucocorticoid Receptors
Pathway
Checkpoint
RNA
Kidney
Modulator
Modulators
Tumor Suppressor Protein p53
Receptor
Target
Activation
Genes
RNA-Binding Proteins

Keywords

  • Alternative splicing
  • GR
  • Kidney cancer
  • Linear regression
  • MDM2
  • TP53
  • Transcriptional regulation

ASJC Scopus subject areas

  • Structural Biology
  • Modeling and Simulation
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics

Cite this

Roles of alternative splicing in modulating transcriptional regulation. / Li, Jin; Wang, Yang; Rao, Xi; Wang, Yue; Feng, Weixing; Liang, Hong; Liu, Yunlong.

In: BMC Systems Biology, Vol. 11, 89, 03.10.2017.

Research output: Contribution to journalArticle

Li, Jin ; Wang, Yang ; Rao, Xi ; Wang, Yue ; Feng, Weixing ; Liang, Hong ; Liu, Yunlong. / Roles of alternative splicing in modulating transcriptional regulation. In: BMC Systems Biology. 2017 ; Vol. 11.
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