Modulator-Dependent RBPs Changes Alternative Splicing Outcomes in Kidney Cancer

Alternative splicing alterations can contribute to human disease. The ability of an RNA-binding protein to regulate alternative splicing outcomes can be modulated by a variety of genetic and epigenetic mechanisms. In this study, we use a computational framework to investigate the roles of certain genes, termed modulators, on changing RBPs’ effect on splicing regulation. A total of 1,040,254 modulator-mediated RBP-splicing interactions were identified, including 137 RBPs, 4,309 splicing events and 2,905 modulator candidates from TCGA-KIRC RNA sequencing data. Modulators function categories were defined according to the correlation changes between RBPs expression and their targets splicing outcomes. QKI, as one of the RBPs influencing the most splicing events, attracted our attention in this study: 2,014 changing triplets were identified, including 1,101 modulators and 187 splicing events. Pathway enrichment analysis showed that QKI splicing targets were enriched in tight junction pathway, endocytosis and MAPK signaling pathways, all of which are highly associated with cancer development and progression. This is the first instance of a comprehensive study on how alternative splicing outcomes changes are associated with different expression level of certain proteins, even though they were regulated by the same RBP. Our work may provide a novel view on understanding alternative splicing mechanisms in kidney cancer.

[1]  Ju-Han Lee,et al.  Loss of CDC14B expression in clear cell renal cell carcinoma: meta-analysis of microarray data sets. , 2014, American journal of clinical pathology.

[2]  The Gene Ontology Consortium,et al.  Expansion of the Gene Ontology knowledgebase and resources , 2016, Nucleic Acids Res..

[3]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[4]  Guang-chun Wang,et al.  NR1B2 suppress kidney renal clear cell carcinoma (KIRC) progression by regulation of LATS 1/2-YAP signaling , 2019, Journal of Experimental & Clinical Cancer Research.

[5]  R. Wilson,et al.  Modernizing Reference Genome Assemblies , 2011, PLoS biology.

[6]  M. Ladomery,et al.  WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. , 2011, Cancer cell.

[7]  M. Karno,et al.  Renal cell carcinoma. , 1956, Bulletin. Tufts-New England Medical Center.

[8]  J. Cheville,et al.  A p120 Catenin Isoform Switch Affects Rho Activity, Induces Tumor Cell Invasion, and Predicts Metastatic Disease* , 2008, Journal of Biological Chemistry.

[9]  Charles Swanton,et al.  Renal cell carcinoma , 2017, Nature Reviews Disease Primers.

[10]  Yanmei Xu,et al.  Mechanism of alternative splicing and its regulation (Review) , 2015 .

[11]  Yang Wang,et al.  Roles of alternative splicing in modulating transcriptional regulation , 2017, BMC Systems Biology.

[12]  Michael Q. Zhang,et al.  HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. , 2014, Cell reports.

[13]  Yulun Huang,et al.  Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling , 2016, Cell Death and Disease.

[14]  P. Stadler,et al.  In vitro iCLIP-based modeling uncovers how the splicing factor U2AF2 relies on regulation by cofactors , 2018, Genome research.

[15]  S. Tseng,et al.  Nuclear p120 catenin unlocks mitotic block of contact-inhibited human corneal endothelial monolayers without disrupting adherent junctions , 2012, Journal of Cell Science.

[16]  M. Swanson,et al.  RNA mis-splicing in disease , 2015, Nature Reviews Genetics.

[17]  Yuan Wang,et al.  Identification and characterization of lncRNA mediated transcriptional dysregulation dictates lncRNA roles in glioblastoma , 2016, Oncotarget.

[18]  A. Jemal,et al.  Cancer statistics, 2019 , 2019, CA: a cancer journal for clinicians.

[19]  Shalini Oberdoerffer,et al.  Co-transcriptional regulation of alternative pre-mRNA splicing. , 2012, Biochimica et biophysica acta.

[20]  M. Ikura,et al.  Dynamic and Static Interactions between p120 Catenin and E-Cadherin Regulate the Stability of Cell-Cell Adhesion , 2010, Cell.

[21]  R. Figlin,et al.  Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. , 2003, The Urologic clinics of North America.

[22]  Alejandro Velázquez-Cruz,et al.  RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate , 2017, Front. Mol. Biosci..

[23]  Somnath Mondal.  RNA Binding , 2020, Definitions.

[24]  Santhilata Kuppili Venkata,et al.  The Network of Cancer Genes (NCG): a comprehensive catalogue of known and candidate cancer genes from cancer sequencing screens , 2018, Genome Biology.

[25]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[26]  The Gene Ontology Consortium.  Expansion of the Gene Ontology knowledgebase and resources , 2016, Nucleic Acids Res..

[27]  Eric L Van Nostrand,et al.  RBP-Maps enables robust generation of splicing regulatory maps , 2018, RNA.

[28]  D. Licatalosi,et al.  Integrative Modeling Defines the Nova Splicing-Regulatory Network and Its Combinatorial Controls , 2010, Science.

[29]  F. Rousset,et al.  RBFOX2 Is an Important Regulator of Mesenchymal Tissue-Specific Splicing in both Normal and Cancer Tissues , 2012, Molecular and Cellular Biology.

[30]  Jian-Ting Shi,et al.  Long non-coding RNA LINC00174 promotes glycolysis and tumor progression by regulating miR-152-3p/SLC2A1 axis in glioma , 2019, Journal of Experimental & Clinical Cancer Research.

[31]  Robert Castelo,et al.  Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition. , 2005, Molecular cell.

[32]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[33]  Bronwen L. Aken,et al.  GENCODE: The reference human genome annotation for The ENCODE Project , 2012, Genome research.

[34]  K. Thumanu,et al.  YAP as a key regulator of adipo-osteogenic differentiation in human MSCs , 2019, Stem Cell Research & Therapy.

[35]  Gene W. Yeo,et al.  Robust transcriptome-wide discovery of RNA binding protein binding sites with enhanced CLIP (eCLIP) , 2016, Nature Methods.

[36]  Xinshu Xiao,et al.  Analysis and design of RNA sequencing experiments for identifying RNA editing and other single-nucleotide variants. , 2013, RNA.

[37]  Mariano J. Alvarez,et al.  Genome-wide Identification of Post-translational Modulators of Transcription Factor Activity in Human B-Cells , 2009, Nature Biotechnology.

[38]  G. Mickisch,et al.  Principles of nephrectomy for malignant disease , 2002, BJU international.

[39]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[40]  G. Schiera,et al.  Regulation of mRNA transport, localization and translation in the nervous system of mammals (Review) , 2014, International journal of molecular medicine.

[41]  F. Baralle,et al.  Alternative splicing as a regulator of development and tissue identity , 2017, Nature Reviews Molecular Cell Biology.

[42]  Yan Wang,et al.  Mechanism of alternative splicing and its regulation. , 2015, Biomedical reports.

[43]  M. Ikura,et al.  Dynamic and Static Interactions between p 120 Catenin and E-Cadherin Regulate the Stability of Cell-Cell Adhesion , 2010 .

[44]  Joshua L. Payne,et al.  RNA-mediated gene regulation is less evolvable than transcriptional regulation , 2018, Proceedings of the National Academy of Sciences.

[45]  S. Gerstberger,et al.  A census of human RNA-binding proteins , 2014, Nature Reviews Genetics.

[46]  Zhongming Zhao,et al.  TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes , 2015, Nucleic Acids Res..

[47]  賢治 高橋,et al.  膵癌とlong non-coding RNA , 2016 .

[48]  Yuanting Gu,et al.  Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway , 2019, Journal of Experimental & Clinical Cancer Research.

[49]  J. Valcárcel,et al.  RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. , 2013, Molecular cell.

[50]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[51]  Chris Sander,et al.  Discovering modulators of gene expression , 2010, Nucleic acids research.

[52]  E. Jankowsky,et al.  Specificity and nonspecificity in RNA–protein interactions , 2015, Nature Reviews Molecular Cell Biology.

[53]  M. Ladomery.  Aberrant Alternative Splicing Is Another Hallmark of Cancer , 2013, International journal of cell biology.