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Large-Scale Analysis of Genome and Transcriptome Alterations in Multiple Tumors Unveils Novel Cancer-Relevant Splicing Networks
Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Research Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks Endre Sebestyén,1,5 Babita Singh,1,5 Belén Miñana,1,2 Amadís Pagès,1 Francesca Mateo,3 Miguel Angel Pujana,3 Juan Valcárcel,1,2,4 and Eduardo Eyras1,4 1Universitat Pompeu Fabra, E08003 Barcelona, Spain; 2Centre for Genomic Regulation, E08003 Barcelona, Spain; 3Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), E08908 L’Hospitalet del Llobregat, Spain; 4Catalan Institution for Research and Advanced Studies, E08010 Barcelona, Spain Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We system- atically analyzed mutation, copy number, and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alter- natively spliced sequences. Our comprehensive study reveals widespread alterations in the expression of RBP genes, as well as novel mutations and copy number variations in association with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, the altered splicing patterns in several tumor types recapitulate those of undifferen- tiated cells. These patterns are predicted to be mainly controlled by MBNL1 and involve multiple cancer drivers, including the mitotic gene NUMA1. We show that NUMA1 alternative splicing induces enhanced cell proliferation and centrosome am- plification in nontumorigenic mammary epithelial cells. -
Dynamic Control of Enhancer Activity Drives Stage-Specific Gene
ARTICLE https://doi.org/10.1038/s41467-019-09513-2 OPEN Dynamic control of enhancer activity drives stage-specific gene expression during flower morphogenesis Wenhao Yan 1,7, Dijun Chen 1,2,7, Julia Schumacher 1,2, Diego Durantini2,5, Julia Engelhorn3,6, Ming Chen4, Cristel C. Carles 3 & Kerstin Kaufmann 1 fi 1234567890():,; Enhancers are critical for developmental stage-speci c gene expression, but their dynamic regulation in plants remains poorly understood. Here we compare genome-wide localization of H3K27ac, chromatin accessibility and transcriptomic changes during flower development in Arabidopsis. H3K27ac prevalently marks promoter-proximal regions, suggesting that H3K27ac is not a hallmark for enhancers in Arabidopsis. We provide computational and experimental evidence to confirm that distal DNase І hypersensitive sites are predictive of enhancers. The predicted enhancers are highly stage-specific across flower development, significantly associated with SNPs for flowering-related phenotypes, and conserved across crucifer species. Through the integration of genome-wide transcription factor (TF) binding datasets, we find that floral master regulators and stage-specific TFs are largely enriched at developmentally dynamic enhancers. Finally, we show that enhancer clusters and intronic enhancers significantly associate with stage-specific gene regulation by floral master TFs. Our study provides insights into the functional flexibility of enhancers during plant devel- opment, as well as hints to annotate plant enhancers. 1 Department for Plant Cell and Molecular Biology, Institute for Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany. 2 Institute for Biochemistry and Biology, University of Potsdam, 14476 Potsdam, Germany. 3 Université Grenoble Alpes (UGA), CNRS, CEA, INRA, IRIG-LPCV, 38000 Grenoble, France, 38000 Grenoble, France. -
Sanjay Kumar Gupta
The human CCHC-type Zinc Finger Nucleic Acid Binding Protein (CNBP) binds to the G-rich elements in target mRNA coding sequences and promotes translation Das humane CCHC-Typ-Zinkfinger-Nukleinsäure-Binde-Protein (CNBP) bindet an G-reiche Elemente in der kodierenden Sequenz seiner Ziel-mRNAs und fördert deren Translation Doctoral thesis for a doctoral degree at the Graduate School of Life Sciences, Julius-Maximilians-Universität WürzBurg, Section: Biomedicine suBmitted By Sanjay Kumar Gupta from Varanasi, India WürzBurg, 2016 1 Submitted on: …………………………………………………………..…….. Office stamp Members of the Promotionskomitee: Chairperson: Prof. Dr. Alexander Buchberger Primary Supervisor: Dr. Stefan Juranek Supervisor (Second): Prof. Dr. Utz Fischer Supervisor (Third): Dr. Markus Landthaler Date of Public Defence: …………………………………………….………… Date of Receipt of Certificates: ………………………………………………. 2 Summary The genetic information encoded with in the genes are transcribed and translated to give rise to the functional proteins, which are building block of a cell. At first, it was thought that the regulation of gene expression particularly occurs at the level of transcription By various transcription factors. Recent discoveries have shown the vital role of gene regulation at the level of RNA also known as post-transcriptional gene regulation (PTGR). Apart from non-coding RNAs e.g. micro RNAs, various RNA Binding proteins (RBPs) play essential role in PTGR. RBPs have been implicated in different stages of mRNA life cycle ranging from splicing, processing, transport, localization and decay. In last 20 years studies have shown the presence of hundreds of RBPs across eukaryotic systems many of which are widely conserved. Given the rising numBer of RBPs and their link to human diseases it is quite evident that RBPs have major role in cellular processes and their regulation. -
An in Vivo Screen Identifies PYGO2 As a Driver for Metastatic Prostate Cancer
Published OnlineFirst May 16, 2018; DOI: 10.1158/0008-5472.CAN-17-3564 Cancer Molecular Cell Biology Research An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer Xin Lu1,2,3, Xiaolu Pan1, Chang-Jiun Wu4, Di Zhao1, Shan Feng2, Yong Zang5, Rumi Lee1, Sunada Khadka1, Samirkumar B. Amin4, Eun-Jung Jin6, Xiaoying Shang1, Pingna Deng1,Yanting Luo2,William R. Morgenlander2, Jacqueline Weinrich2, Xuemin Lu2, Shan Jiang7, Qing Chang7, Nora M. Navone8, Patricia Troncoso9, Ronald A. DePinho1, and Y. Alan Wang1 Abstract Advanced prostate cancer displays conspicuous chromosomal inhibits prostate cancer cell invasion in vitro and progression of instability and rampant copy number aberrations, yet the identity primary tumor and metastasis in vivo. In clinical samples, PYGO2 of functional drivers resident in many amplicons remain elusive. upregulation associated with higher Gleason score and metastasis Here, we implemented a functional genomics approach to identify to lymph nodes and bone. Silencing PYGO2 expression in patient- new oncogenes involved in prostate cancer progression. Through derived xenograft models impairs tumor progression. Finally, integrated analyses of focal amplicons in large prostate cancer PYGO2 is necessary to enhance the transcriptional activation in genomic and transcriptomic datasets as well as genes upregulated response to ligand-induced Wnt/b-catenin signaling. Together, our in metastasis, 276 putative oncogenes were enlisted into an in vivo results indicate that PYGO2 functions as a driver oncogene in the gain-of-function tumorigenesis screen. Among the top positive 1q21.3 amplicon and may serve as a potential prognostic bio- hits, we conducted an in-depth functional analysis on Pygopus marker and therapeutic target for metastatic prostate cancer. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
GIGANTUS1 (GTS1), a Member of Transducin/WD40 Protein
Gachomo et al. BMC Plant Biology 2014, 14:37 http://www.biomedcentral.com/1471-2229/14/37 RESEARCH ARTICLE Open Access GIGANTUS1 (GTS1), a member of Transducin/WD40 protein superfamily, controls seed germination, growth and biomass accumulation through ribosome-biogenesis protein interactions in Arabidopsis thaliana Emma W Gachomo1,2†, Jose C Jimenez-Lopez3,4†, Lyla Jno Baptiste1 and Simeon O Kotchoni1,2* Abstract Background: WD40 domains have been found in a plethora of eukaryotic proteins, acting as scaffolding molecules assisting proper activity of other proteins, and are involved in multi-cellular processes. They comprise several stretches of 44-60 amino acid residues often terminating with a WD di-peptide. They act as a site of protein-protein interactions or multi-interacting platforms, driving the assembly of protein complexes or as mediators of transient interplay among other proteins. In Arabidopsis, members of WD40 protein superfamily are known as key regulators of plant-specific events, biologically playing important roles in development and also during stress signaling. Results: Using reverse genetic and protein modeling approaches, we characterize GIGANTUS1 (GTS1), a new member of WD40 repeat protein in Arabidopsis thaliana and provide evidence of its role in controlling plant growth development. GTS1 is highly expressed during embryo development and negatively regulates seed germination, biomass yield and growth improvement in plants. Structural modeling analysis suggests that GTS1 folds into a β-propeller with seven pseudo symmetrically arranged blades around a central axis. Molecular docking analysis shows that GTS1 physically interacts with two ribosomal protein partners, a component of ribosome Nop16, and a ribosome-biogenesis factor L19e through β-propeller blade 4 to regulate cell growth development. -
Immunoprecipitation and Mass Spectrometry Defines an Extensive
BRES : 44759 Model7 pp: À 1221ðcol:fig: : NILÞ brain research ] ( ]]]]) ]]]– ]]] Available online at www.sciencedirect.com 121 122 123 124 125 126 www.elsevier.com/locate/brainres 127 128 129 Review 130 131 fi 132 Immunoprecipitation and mass spectrometry de nes 133 – 134 an extensive RBM45 protein protein interaction 135 Q2 136 network 137 138 a a,b a a c 139 Yang Li , Mahlon Collins , Jiyan An , Rachel Geiser , Tony Tegeler , c c c a,b,n 140 Q1 Kristine Tsantilas , Krystine Garcia , Patrick Pirrotte , Robert Bowser 141 aDivisions of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 142 Phoenix, AZ 85013, USA 143 bUniversity of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA 144 cCenter for Proteomics, TGen (Translational Genomics Research Institute), Phoenix, AZ 85004, USA 145 146 147 article info abstract 148 149 Article history: The pathological accumulation of RNA-binding proteins (RBPs) within inclusion bodies is a 150 Received 30 January 2016 hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration 151 Received in revised form (FTLD). RBP aggregation results in both toxic gain and loss of normal function. Determining 152 25 February 2016 the protein binding partners and normal functions of disease-associated RBPs is necessary 153 Accepted 28 February 2016 to fully understand molecular mechanisms of RBPs in disease. Herein, we characterized 154 the protein–protein interactions (PPIs) of RBM45, a RBP that localizes to inclusions in ALS/ 155 – fi Keywords: FTLD. Using immunoprecipitation coupled to mass spectrometry (IP MS), we identi ed 132 156 fi RBM45 proteins that speci cally interact with RBM45 within HEK293 cells. -
Eef2k) Natural Product and Synthetic Small Molecule Inhibitors for Cancer Chemotherapy
International Journal of Molecular Sciences Review Progress in the Development of Eukaryotic Elongation Factor 2 Kinase (eEF2K) Natural Product and Synthetic Small Molecule Inhibitors for Cancer Chemotherapy Bin Zhang 1 , Jiamei Zou 1, Qiting Zhang 2, Ze Wang 1, Ning Wang 2,* , Shan He 1 , Yufen Zhao 2 and C. Benjamin Naman 1,* 1 Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo 315800, China; [email protected] (B.Z.); [email protected] (J.Z.); [email protected] (Z.W.); [email protected] (S.H.) 2 Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China; [email protected] (Q.Z.); [email protected] (Y.Z.) * Correspondence: [email protected] (N.W.); [email protected] (C.B.N.) Abstract: Eukaryotic elongation factor 2 kinase (eEF2K or Ca2+/calmodulin-dependent protein kinase, CAMKIII) is a new member of an atypical α-kinase family different from conventional protein kinases that is now considered as a potential target for the treatment of cancer. This protein regulates the phosphorylation of eukaryotic elongation factor 2 (eEF2) to restrain activity and inhibit the elongation stage of protein synthesis. Mounting evidence shows that eEF2K regulates the cell cycle, autophagy, apoptosis, angiogenesis, invasion, and metastasis in several types of cancers. The Citation: Zhang, B.; Zou, J.; Zhang, expression of eEF2K promotes survival of cancer cells, and the level of this protein is increased in Q.; Wang, Z.; Wang, N.; He, S.; Zhao, many cancer cells to adapt them to the microenvironment conditions including hypoxia, nutrient Y.; Naman, C.B. -
BOP1 (A-18): Sc-87884
SAN TA C RUZ BI OTEC HNOL OG Y, INC . BOP1 (A-18): sc-87884 BACKGROUND CHROMOSOMAL LOCATION Predominantly localized to the nucleolus, BOP1 (Block of proliferation 1 pro - Genetic locus: BOP1 (human) mapping to 8q24.3; Bop1 (mouse) mapping to tein) is a 746 amino acid highly conserved non-ribosomal protein that is in- 15 D3. volved in ribosome biogenesis. Truncation of the amino terminus of BOP1 leads to cell growth arrest in the G 1 phase and specific inhibition of 28S and SOURCE 5.8S rRNA synthesis, as well as a deficit in the cytosolic 60S ribosomal sub - BOP1 (A-18) is an affinity purified rabbit polyclonal antibody raised against a unit. This suggests that BOP1 is involved in the formation of mature rRNAs peptide mapping within an internal region of BOP1 of human origin. and in the biogenesis of the 60S ribosomal subunit. BOP1 physically inter acts with pescadillo (a protein involved in cell proliferation) and enables efficient PRODUCT incorporation of pescadillo into the nucleolar preribosomal complexes, there - by affecting rRNA maturation and the cell cycle. The BOP1-pescadillo com - Each vial contains 100 µg IgG in 1.0 ml of PBS with < 0.1% sodium azide plex is also necessary for biogenesis of 60S ribosomal subunits. Deregulation and 0.1% gelatin. of BOP1 may lead to colorectal tumorigenesis. Blocking peptide available for competition studies, sc-87884 P, (100 µg peptide in 0.5 ml PBS containing < 0.1% sodium azide and 0.2% BSA). REFERENCES 1. Strezoska, Z., Pestov, D.G. and Lau, L.F. 2000. -
Characterizing G-Quadruplex Mediated Regulation of the Amyloid Precursor Protein Expression by Ezekiel Matthew David Crenshaw Oc
I Characterizing G-Quadruplex Mediated Regulation of the Amyloid Precursor Protein Expression By Ezekiel Matthew David Crenshaw October, 2016 A Dissertation Presented to the Faculty of Drexel University Department of Biology In partial fulfillment of the Requirements for the Degree of Ph.D. Daniel Marenda, Ph.D. (Chair) Elias Spiliotis, Ph.D. Associate Professor, Associate Professor, Director, Graduate Student Program Director, Cell Imaging Center Co-Director, Cell Imaging Center Dept. Biology Dept. Biology Drexel University Drexel University Tali Gidalevitz, Ph.D. Aleister Saunders, Ph.D. (Advisor) Assistant Professor, Dept. Biology Associate Professor, Drexel University Director of the RNAi Resource Center, Dept. Biology Jeff Twiss, Ph.D. Senior Vice Provost for Research, Drexel University Professor, SmartState Chair, Childhood Neurotherapeutics Michael Akins, Ph.D.(Co-Advisor) Dept. Biology University of South Carolina Assistant Professor, Dept. Biology Drexel University II Acknowledgements Proverbs 3:5-6, “Trust in the Lord with all thine heart and lean not unto thine own understanding. In all thine ways acknowledge Him and He shall direct thy paths” I want to start off my acknowledging my LORD, who is known by many names. He is El Elyon, The Most High God; He is YAHWEH Shammah, for He has been there for me; He is YAHWEH Yireh, for He has provided for all of my needs; He is YAHWEH Shalom, for He is my peace. He is Yeshua Ha Mashiach, for He is my Savior. Coming from humble beginnings, my faith in the LORD has been the source of strength and encouragement to overcome the many obstacles I faced growing up, as well as in my pursuit for my Ph.D. -
Genes with 5' Terminal Oligopyrimidine Tracts Preferentially Escape Global Suppression of Translation by the SARS-Cov-2 NSP1 Protein
Downloaded from rnajournal.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Genes with 5′ terminal oligopyrimidine tracts preferentially escape global suppression of translation by the SARS-CoV-2 Nsp1 protein Shilpa Raoa, Ian Hoskinsa, Tori Tonna, P. Daniela Garciaa, Hakan Ozadama, Elif Sarinay Cenika, Can Cenika,1 a Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA 1Corresponding author: [email protected] Key words: SARS-CoV-2, Nsp1, MeTAFlow, translation, ribosome profiling, RNA-Seq, 5′ TOP, Ribo-Seq, gene expression 1 Downloaded from rnajournal.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract Viruses rely on the host translation machinery to synthesize their own proteins. Consequently, they have evolved varied mechanisms to co-opt host translation for their survival. SARS-CoV-2 relies on a non-structural protein, Nsp1, for shutting down host translation. However, it is currently unknown how viral proteins and host factors critical for viral replication can escape a global shutdown of host translation. Here, using a novel FACS-based assay called MeTAFlow, we report a dose-dependent reduction in both nascent protein synthesis and mRNA abundance in cells expressing Nsp1. We perform RNA-Seq and matched ribosome profiling experiments to identify gene-specific changes both at the mRNA expression and translation level. We discover that a functionally-coherent subset of human genes are preferentially translated in the context of Nsp1 expression. These genes include the translation machinery components, RNA binding proteins, and others important for viral pathogenicity. Importantly, we uncovered a remarkable enrichment of 5′ terminal oligo-pyrimidine (TOP) tracts among preferentially translated genes. -
Comparative Interactomics Analysis of Different ALS-Associated Proteins
Acta Neuropathol (2016) 132:175–196 DOI 10.1007/s00401-016-1575-8 ORIGINAL PAPER Comparative interactomics analysis of different ALS‑associated proteins identifies converging molecular pathways Anna M. Blokhuis1 · Max Koppers1,2 · Ewout J. N. Groen1,2,9 · Dianne M. A. van den Heuvel1 · Stefano Dini Modigliani4 · Jasper J. Anink5,6 · Katsumi Fumoto1,10 · Femke van Diggelen1 · Anne Snelting1 · Peter Sodaar2 · Bert M. Verheijen1,2 · Jeroen A. A. Demmers7 · Jan H. Veldink2 · Eleonora Aronica5,6 · Irene Bozzoni3 · Jeroen den Hertog8 · Leonard H. van den Berg2 · R. Jeroen Pasterkamp1 Received: 22 January 2016 / Revised: 14 April 2016 / Accepted: 15 April 2016 / Published online: 10 May 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Amyotrophic lateral sclerosis (ALS) is a dev- OPTN and UBQLN2, in which mutations caused loss or astating neurological disease with no effective treatment gain of protein interactions. Several of the identified inter- available. An increasing number of genetic causes of ALS actomes showed a high degree of overlap: shared binding are being identified, but how these genetic defects lead to partners of ATXN2, FUS and TDP-43 had roles in RNA motor neuron degeneration and to which extent they affect metabolism; OPTN- and UBQLN2-interacting proteins common cellular pathways remains incompletely under- were related to protein degradation and protein transport, stood. To address these questions, we performed an inter- and C9orf72 interactors function in mitochondria. To con- actomic analysis to identify binding partners of wild-type firm that this overlap is important for ALS pathogenesis, (WT) and ALS-associated mutant versions of ATXN2, we studied fragile X mental retardation protein (FMRP), C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal one of the common interactors of ATXN2, FUS and TDP- cells.