Luiz O.F. Penalva, PhD
Greehey Children’s Cancer Research Institute
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.
Yi C, Li G, Ivanov DN, Wang Z, Velasco MX, Hernández G, Kaundal S, Villarreal J, Gupta YK, Qiao M, Hubert CG, Hart MJ, Penalva LOF. RNA Biol. 2018;15 (11):1420-1432. doi: 10.1080/15476286.2018.1539607. Epub 2018 Nov 18.
Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity.
Uchuya-Castillo J, Aznar N, Frau C, Martinez P, Le Nevé C, Marisa L, Penalva LOF, Laurent-Puig P, Puisieux A, Scoazec JY, Samarut J, Ansieau S, Plateroti M.
Oncotarget 2018 Jul 24;9(57):30979-30996. doi: 10.18632/oncotarget.25741. eCollection 2018 Jul 24.
Correa BRS, Hu J, Penalva LOF, Schlegel R, Rimm DL, Galante PAF, Agarwal S.
Sci Rep. 2018 Mar 6;8(1):4097. doi: 10.1038/s41598-018-22427-1.
Sanford JR, Penalva LOF.
Genome Biol. 2017 Nov 29;18(1):227. doi: 10.1186/s13059-017-1360-6.
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.
Penalva LO, Sanford JR.
Hum Genet. 2017 Sep;136(9):1013-1014. doi: 10.1007/s00439-017-1841-4.
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.
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.
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.
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.
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.
Bahrami-Samani E, Penalva LO, Smith AD, Uren PJ.
Nucleic Acids Res. 2015 Jan;43(1):95-103. doi: 10.1093/nar/gku1288.
CSBL 5024-001 Genomics
CSBL 6090-001 Seminar
IBMS 6090-3CB Seminar
IBMS 6090-4CGM Seminar
Department: Cell Systems & Anatomy
Location: Greehey CCRI
SUPORT OUR RESEARCH
RNA binding proteins (RBPs) and miRNAs play major roles in gene expression by controlling all stages of mRNA processing, its transport, localization, decay and translation. My laboratory studies these two regulators from a global perspective. We use a combination of genomics, systems biology, biochemistry, bioinformatics and molecular biology to investigate the networks formed by RNA binding proteins, miRNAs and their target genes and evaluate their impact on biological processes, cancer and disease states. I am particularly interested in the neuronal tissue and the analysis of gene regulators implicated in both differentiation and brain tumor development.
in brain tumor development
Our lab is interested in RNA-binding proteins acting at the intersection neurogenesis-brain tumor development. For the last ten years, the major highlight of our work has been the stem cell protein Musashi1 (Msi1) and its participation in medulloblastoma and glioblastoma. We showed that Musashi1 is highly expressed in the high risk medulloblastoma sub-groups 3 and 4 and linked to poor prognosis. We have established that Msi1 regulates multiple cancer-relevant processes including apoptosis, cell cycle, proliferation, migration, invasion and adhesion via a complex network of target genes. Msi1 expression levels influence both radio- and chemo-resistance and its function is required for the survival of tumor initiating cells. Convinced that Msi1 is a critical oncogenic factor, we have recently developed an inhibitor that blocks Msi1 RNA binding domains. We are currently working to improve its structure and drug properties, aiming its future use in cancer therapy
in neurogenesis and brain tumor development
miRNAs function as important regulatory switches, influencing cell fate decisions and tumor development. miR-124, miR-128 and miR-137 are among the top-expressed miRNAs in the brain. They display parallel increase in expression as cells differentiate and their function is absolutely required for neuronal production. These three miRNAs are often repressed in glioblastoma and suggested to work as tumor suppressors. Our results indicate that miR-124, -128 and -137 act synergistically and control highly overlapping target sets. Interestingly, we also determined that miR-124, -128 and -137 share a large number of targets with Musashi1. In the antagonist model we propose to establish, Musashi1 and these three miRNAs have opposite impact on the expression of shared targets (activation by Musashi1 vs. repression by miR-124, -128 and -137). The concentration of each regulator would ultimately influence this network and neural stem cell fate with the options of self-renewal, differentiation or tumor development.
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.
Genome-scale knowledge of translational regulation has lagged behind that of transcription, despite a central role determining cell phenotype, and major implications for numerous diseases and cancer. The assay of choice for global gene expression profiling is RNA-seq, which makes sense for understanding transcriptional control. But levels of mRNA in a cell explain only a fraction of observed protein levels, and much of the remainder is due to translational control. Ribosome profiling (RP) or Ribo-seq is a novel genomic approach that delivers quantitative information on the number and behavior of ribosomes, and gives profiles of gene expression much more closely linked to actual protein levels. We are using Ribo-seq aligned with computational tools to identify alterations in translation regulation in cancer cells and study its behavior upon drug and radiation treatments. We are also interested in examining the role of aberrantly expressed ribosomal proteins in tumor development and determine if they affect translation in specific fashions.
WHO WE ARE
Penalva’s LAB complete publication list