PROJECT 3: Alternative splicing regulation in brain tumor development
Analysis of several hundred glioblastoma samples compiled by the TCGA (The Cancer Genome Atlas) produced an extensive transcriptomic map, identified prevalent chromosomal alterations and defined important driver mutations. However, as of today, clinical trials based on these results have not delivered an improvement on outcome. Therefore, we decided to characterize other regulatory routes known for playing a role in tumor relapse and response to treatment.
We selected splicing regulation for the following reasons:
- Alternative splicing affects 90% of the transcriptome and is an important source for transcript variation and gene regulation;
- Numerous genes involved in apoptosis, proliferation, migration and DNA repair display cancer specific splicing isoforms with functions distinct from the ones in normal tissue;
- Mutations and alterations in splicing factors are highly prevalent in multiple cancers and can act as tumor drivers;
- Genomic instability, a common characteristic of cancer, can be induced by splicing defects;
- The splicing machinery is targetable: there are numerous examples of drugs that either inhibit splicing factors or promote changes in splicing;
- Importantly, no comprehensive studies have been performed to study splicing regulation in GBM.
Using resources from TCGA (The Cancer Genome Atlas) and GTex (Genotype-Tissue Expression), we have analyzed the expression profile of splicing regulators in normal and brain tumor tissues and produced detailed maps of splicing alterations in cancer cells. Our current plans are to link splicing regulators to oncogenic signals required for transformation, identify critical splicing isoforms and evaluate their contribution to gliomagenesis.
Dr. Luiz O. Penalva received his PhD from Universidad Autonoma de Madrid, Spain and worked as a post-doctoral fellow at the European Molecular Biology Laboratories (EMBL-Germany) and Duke University. He has been a principal investigator at Greehey Children's Cancer Research Institute since 2004 and is a member of the Department of Cell Systems and Anatomy.
RNA biology, genomics, RNA binding proteins, miRNAs, alternative splicing, translation, brain tumors
- The 3' end of the story: deciphering combinatorial interactions that control mRNA fate. Sanford JR, Penalva LOF. Genome Biol. 2017 Nov 29;18(1):227. doi: 10.1186/s13059-017-1360-6.Z
- MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1. Cirilo PDR, de Sousa Andrade LN, Corrêa BRS, Qiao M, Furuya TK, Chammas R, Penalva LOF. BMC Cancer. 2017 Nov 10;17(1):750. doi: 10.1186/s12885-017-3721-7.
- From mechanisms to therapy: RNA processing's impact on human genetics. Penalva LO, Sanford JR. Hum Genet. 2017 Sep;136(9):1013-1014. doi: 10.1007/s00439-017-1841-4.
- RNA processing as an alternative route to attack glioblastoma. Marcelino Meliso F, Hubert CG, Favoretto Galante PA, Penalva LO. Hum Genet. 2017 Sep;136(9):1129-1141. doi: 10.1007/s00439-017-1819-2.
- Riborex: fast and flexible identification of differential translation from Ribo-seq data. Li W, Wang W, Uren PJ, Penalva LOF, Smith AD. Bioinformatics. 2017 Jun 1;33(11):1735-1737. doi: 10.1093/bioinformatics/btx047.
- Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit. de Araujo PR, Gorthi A, da Silva AE, Tonapi SS, Vo DT, Burns SC, Qiao M, Uren PJ, Yuan ZM, Bishop AJ, Penalva LO. Am J Pathol. 2016 Sep;186(9):2271-8. doi: 10.1016/j.ajpath.2016.05.020.
- Functional genomics analyses of RNA-binding proteins reveal the splicing regulator SNRPB as an oncogenic candidate in glioblastoma. Correa BR, de Araujo PR, Qiao M, Burns SC, Chen C, Schlegel R, Agarwal S, Galante PA, Penalva LO. Genome Biol. 2016 Jun 10;17(1):125. doi: 10.1186/s13059-016-0990-4.
- IGF2BP3 Modulates the Interaction of Invasion-Associated Transcripts with RISC. Ennajdaoui H, Howard JM, Sterne-Weiler T, Jahanbani F, Coyne DJ, Uren PJ, Dargyte M, Katzman S, Draper JM, Wallace A, Cazarez O, Burns SC, Qiao M, Hinck L, Smith AD, Toloue MM, Blencowe BJ, Penalva LO, Sanford JR. Cell Rep. 2016 May 31;15(9):1876-83. doi: 10.1016/j.celrep.2016.04.083.
- High-throughput analyses of hnRNP H1 dissects its multi-functional aspect. Uren PJ, Bahrami-Samani E, de Araujo PR, Vogel C, Qiao M, Burns SC, Smith AD, Penalva LO. RNA Biol. 2016;13(4):400-11. doi: 10.1080/15476286.2015.1138030.
- miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network. Santos MC, Tegge AN, Correa BR, Mahesula S, Kohnke LQ, Qiao M, Ferreira MA, Kokovay E, Penalva LO. Stem Cells. 2016 Jan;34(1):220-32. doi: 10.1002/stem.2204.
- A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness. Cambuli FM, Correa BR, Rezza A, Burns SC, Qiao M, Uren PJ, Kress E, Boussouar A, Galante PA, Penalva LO, Plateroti M. Stem Cells. 2015 Dec;33(12):3621-34. doi: 10.1002/stem.2202.
- RNA-Binding Protein Musashi1 Is a Central Regulator of Adhesion Pathways in Glioblastoma. Uren PJ, Vo DT, de Araujo PR, Pötschke R, Burns SC, Bahrami-Samani E, Qiao M, de Sousa Abreu R, Nakaya HI, Correa BR, Kühnöl C, Ule J, Martindale JL, Abdelmohsen K, Gorospe M, Smith AD, Penalva LO. Mol Cell Biol. 2015 Sep 1;35(17):2965-78. doi: 10.1128/MCB.00410-15.
- Computational challenges, tools, and resources for analyzing co- and post-transcriptional events in high throughput. Bahrami-Samani E, Vo DT, de Araujo PR, Vogel C, Smith AD, Penalva LO, Uren PJ. Wiley Interdiscip Rev RNA. 2015 May-Jun;6(3):291-310. doi: 10.1002/wrna.1274.
- Leveraging cross-link modification events in CLIP-seq for motif discovery..Bahrami-Samani E, Penalva LO, Smith AD, Uren PJ. Nucleic Acids Res. 2015 Jan;43(1):95-103. doi: 10.1093/nar/gku1288.
- RNA binding protein HuR regulates the expression of ABCA1. Ramírez CM, Lin CS, Abdelmohsen K, Goedeke L, Yoon JH, Madrigal-Matute J, Martin-Ventura JL, Vo DT, Uren PJ, Penalva LO, Gorospe M, Fernández-Hernando C. J Lipid Res. 2014 Jun;55(6):1066-76. doi: 10.1194/jlr.M044925.
- Genomic analyses reveal broad impact of miR-137 on genes associated with malignant transformation and neuronal differentiation in glioblastoma cells. Tamim S, Vo DT, Uren PJ, Qiao M, Bindewald E, Kasprzak WK, Shapiro BA, Nakaya HI, Burns SC, Araujo PR, Nakano I, Radek AJ, Kuersten S, Smith AD, Penalva LO. PLoS One. 2014 Jan 22;9(1):e85591. doi: 10.1371/journal.pone.0085591. eCollection 2014.
- WTAP is a novel oncogenic protein in acute myeloid leukemia. Bansal H, Yihua Q, Iyer SP, Ganapathy S, Proia DA, Penalva LO, Uren PJ, Suresh U, Carew JS, Karnad AB, Weitman S, Tomlinson GE, Rao MK, Kornblau SM, Bansal S. Leukemia. 2014 May;28(5):1171-4. doi: 10.1038/leu.2014.16.