Characterizing the Interplay Between Gene Nucleotide Composition Bias

Total Page:16

File Type:pdf, Size:1020Kb

Characterizing the Interplay Between Gene Nucleotide Composition Bias Lemaire et al. Genome Biology (2019) 20:259 https://doi.org/10.1186/s13059-019-1869-y RESEARCH Open Access Characterizing the interplay between gene nucleotide composition bias and splicing Sébastien Lemaire1†, Nicolas Fontrodona1†, Fabien Aubé1†, Jean-Baptiste Claude1, Hélène Polvèche2, Laurent Modolo3, Cyril F. Bourgeois1, Franck Mortreux1 and Didier Auboeuf1* Abstract Background: Nucleotide composition bias plays an important role in the 1D and 3D organization of the human genome. Here, we investigate the potential interplay between nucleotide composition bias and the regulation of exon recognition during splicing. Results: By analyzing dozens of RNA-seq datasets, we identify two groups of splicing factors that activate either about 3200 GC-rich exons or about 4000 AT-rich exons. We show that splicing factor–dependent GC-rich exons have predicted RNA secondary structures at 5′ ss and are dependent on U1 snRNP–associated proteins. In contrast, splicing factor–dependent AT-rich exons have a large number of decoy branch points, SF1- or U2AF2-binding sites and are dependent on U2 snRNP–associated proteins. Nucleotide composition bias also influences local chromatin organization, with consequences for exon recognition during splicing. Interestingly, the GC content of exons correlates with that of their hosting genes, isochores, and topologically associated domains. Conclusions: We propose that regional nucleotide composition bias over several dozens of kilobase pairs leaves a local footprint at the exon level and induces constraints during splicing that can be alleviated by local chromatin organization at the DNA level and recruitment of specific splicing factors at the RNA level. Therefore, nucleotide composition bias establishes a direct link between genome organization and local regulatory processes, like alternative splicing. Keywords: Splicing, Genomic, Chromatin organization, Nucleotide composition bias Introduction [2]. For example, secondary structures at the 5′ ss can hin- Most eukaryotic genes comprise both exons and introns. der the interactions between the 5′ ss and U1 snRNA and Introns are defined at their 5′-end by the 5′ splicing site this structure-dependent constraint can be relaxed by RNA (ss), which interacts with the U1 snRNA, and at their 3′- helicases, such as DDX5 and DDX17 [3–5]. Meanwhile, end, by the branch point (BP; recognized by SF1), the poly- secondary structures at the 3′-end of short introns can re- pyrimidine (Py) tract (recognized by U2AF2 or U2AF65), place the need for U2AF2 [6]. Splicing signals are short and the 3′ ss (recognized by U2AF1 or U2AF35) [1]. SF1 degenerate sequences, and exons are much smaller than and U2AF2 allow the recruitment of the U2 snRNP, which introns. How then are exons precisely defined? How are contains the U2 snRNA that interacts with the BP [1]. Re- bona fide splicing signals distinguished from pseudo- cent large-scale experiments have demonstrated that RNA signals or decoy signals? These questions have been inten- secondary structures frequently occur in the vicinity of sively researched but still remain open. splicing sites and gene-by-gene analyses have demonstrated Many (if not all) exons require a variety of splicing fac- that RNA structures play a direct role in splicing regulation tors to be defined. Splicing factors that belong to differ- ent families of RNA binding proteins, such as the SR and hnRNP families, bind to short degenerate motifs * Correspondence: [email protected] †Sébastien Lemaire, Nicolas Fontrodona and Fabien Aubé contributed either in exons or introns of pre-mRNAs [7]. Splicing equally to this work. factor binding sites are low-complexity sequences com- 1Laboratory of Biology and Modelling of the Cell, Univ Lyon, ENS de Lyon, prising either the same nucleotide or dinucleotide [8–10]. Univ Claude Bernard, CNRS UMR 5239, INSERM U1210, 46 Allée d’Italie Site Jacques Monod, F-69007 Lyon, France Splicing factors modulate the recruitment of different Full list of author information is available at the end of the article spliceosome-associated components [7, 11]. © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lemaire et al. Genome Biology (2019) 20:259 Page 2 of 21 Spliceosome assembly and the splicing process occur Here, we have investigated the relationship between mostly during transcription [11, 12]. In this setting, the the splicing process, gene nucleotide composition bias, velocity of RNA polymerase II (RNAPII) influences exon and chromatin organization at both the local and global recognition in a complex manner, as speeding up tran- levels. We initially identified sets of exons activated by scription elongation can either enhance or repress exon different splicing factors and then demonstrated that inclusion [13]. RNAPII velocity is in turn influenced by analyzing the nucleotide composition bias provided a the local chromatin organization, such as the presence better understanding of the interplay between chromatin of nucleosomes [11, 12]. Nucleosomes are preferentially organization and splicing-related features, which collect- positioned on exons because exons have a higher GC ively affect exon recognition. We propose that nucleo- content than introns, which increases DNA bendability tide composition bias not only contributes to the 1D and [14–17]. In addition, Py tracts (mostly made of Ts) up- 3D genome organization, but has also local conse- stream of exons may form a nucleosome energetic bar- quences at the exon level during the splicing process. rier [14–17]. Nucleosomes influence splicing by slowing down RNAPII in the vicinity of exons and by modulating Results the local recruitment of splicing regulators [11, 12]. In- Splicing factor–dependent GC-rich and AT-rich exons deed, depending on their specific chemical modifications Publicly available RNA-seq datasets generated after (e.g., methylation), histone tails can interact directly or knocking down or overexpressing individual splicing fac- indirectly with splicing factors [18]. Therefore, exon tors across different cell lines were analyzed [28–43] recognition during the splicing process depends on a (Additional file 1: Table S1). Using our recently pub- complex interplay between signals at the DNA level lished FARLINE pipeline, which allows the inclusion rate (e.g., nucleosome positioning) and signals at the RNA of exons from RNA-seq datasets to be quantified [44], level (e.g., splicing factor binding sites). we defined the sets of exons whose inclusion is acti- Genes are not randomly organized across a genome, vated by each of the 33 splicing factors that were and nucleotide composition bias over genomic regions analyzed (Additional file 2: Table S2). We focused on of varying lengths plays an important role in genome splicing factor–activated exons to uncover the splicing- organization at multiple genomic scales. For example, related features characterizing exons whose recognition isochores are large genomic regions (≥ 30 kbps) with a depends on at least one splicing factor. We identified 10, uniform GC content that differs from adjacent regions 707 exons that were activated by at least one splicing [19–21]. Isochores can be classified into five families, factor from the 93,680 exons whose inclusion rate ranging from less than 37% of GC content to more than was quantified by FARLINE across all datasets (see 53% [19–21]. GC-rich isochores have a higher density of the “Materials and methods” section). genes than AT-rich isochores, and genes in GC-rich iso- As expected, splicing factor–activated exons had weaker chores contain smaller introns than genes in AT-rich 3′-and/or5′-splicing site (ss) scores as compared to the isochores [22–24]. In addition, to be associated with median score of human exons (Additional file 3:FigureS1). specific gene features (e.g., intron size), the density of We computed the nucleotide composition of each splicing GC nucleotides in genes has consequences on splicing factor–activated exon (Additional file 3:FigureS2).Note site sequences and on the splicing process [25]. For ex- that we systematically refer to both thymine and uracil as ample, it has been proposed that splicing of short in- “T” to simplify our goal of analyzing sequence-dependent trons in a GC-rich context may occur through the features at both the DNA and RNA levels. In addition, intron definition model, while the splicing of large in- values obtained from splicing factor–activated exons were trons in an AT-rich context may occur through the normalized by the median values measured for human cod- exon definition model [11, 26]. Collectively, these ing exons used as a set of control exons, in order to repre- observations support a model in which the gene archi- sent results in a consistent way. Sets of exons activated by tecture and gene nucleotide composition bias (e.g., GC different splicing factors had a different proportion of GCs or AT content) influence local processes at the exon as compared to the median values of control exons (Fig. 1a, level, such as nucleosome positioning and intron re- Additional file 3: Figure S3a). Interestingly, the GC content moval. As exon recognition also depends on the bind- of splicing factor–activated exons positively correlated with ing to the pre-mRNAs of splicing factors that interact the GC content of their flanking introns (Fig. 1b, upper − with compositionally biased sequences, one interesting panel, P value < 10 16 and Additional file 3:FigureS3d). possibility is that the nature of these splicing factors Accordingly, splicing factor–activated GC- and AT- depends at least in part on the gene nucleotide com- rich exons were flanked by GC- and AT-rich position bias.
Recommended publications
  • The Splicing Factor U2AF1 Contributes to Cancer Progression Through a Noncanonical Role in Translation Regulation
    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation Murali Palangat,1 Dimitrios G. Anastasakis,2 Dennis Liang Fei,3 Katherine E. Lindblad,4 Robert Bradley,5 Christopher S. Hourigan,4 Markus Hafner,2 and Daniel R. Larson1 1Laboratory of Receptor Biology and Gene Expression, National Cancer Insitute, National Institutes of Health, Bethesda, Maryland 20892, USA; 2National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA; 3Weill Cornell Medicine, New York, New York 10065, USA; 4Laboratory of Myeloid Malignancies, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; 5Computational Biology Program, Public Health Sciences and Biological Sciences, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3′ splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing- independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA.
    [Show full text]
  • 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.
    [Show full text]
  • Pan-Cancer Analysis Identifies Mutations in SUGP1 That Recapitulate Mutant SF3B1 Splicing Dysregulation
    Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation Zhaoqi Liua,b,c,1, Jian Zhangd,1, Yiwei Suna,c, Tomin E. Perea-Chambleea,b,c, James L. Manleyd,2, and Raul Rabadana,b,c,2 aProgram for Mathematical Genomics, Columbia University, New York, NY 10032; bDepartment of Systems Biology, Columbia University, New York, NY 10032; cDepartment of Biomedical Informatics, Columbia University, New York, NY 10032; and dDepartment of Biological Sciences, Columbia University, New York, NY 10027 Contributed by James L. Manley, March 2, 2020 (sent for review January 2, 2020; reviewed by Kristen Lynch and Gene Yeo) The gene encoding the core spliceosomal protein SF3B1 is the most also resulted in the same splicing defects observed in SF3B1 frequently mutated gene encoding a splicing factor in a variety of mutant cells (11). hematologic malignancies and solid tumors. SF3B1 mutations in- In addition to SF3B1, other SF-encoding genes have also been duce use of cryptic 3′ splice sites (3′ss), and these splicing errors found to be mutated in hematologic malignancies, e.g., U2AF1, contribute to tumorigenesis. However, it is unclear how wide- SRSF2, and ZRSR2. However, these SF gene mutations do not spread this type of cryptic 3′ss usage is in cancers and what is share common alterations in splicing (1, 3), suggesting that dif- the full spectrum of genetic mutations that cause such missplicing. ferent splicing patterns may contribute to different phenotypes To address this issue, we performed an unbiased pan-cancer anal- of cancers. Because SF3B1 is the most frequently mutated ysis to identify genetic alterations that lead to the same aberrant splicing gene, the splicing defects caused by mutant SF3B1 may SF3B1 splicing as observed with mutations.
    [Show full text]
  • Nuclear PTEN Safeguards Pre-Mrna Splicing to Link Golgi Apparatus for Its Tumor Suppressive Role
    ARTICLE DOI: 10.1038/s41467-018-04760-1 OPEN Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role Shao-Ming Shen1, Yan Ji2, Cheng Zhang1, Shuang-Shu Dong2, Shuo Yang1, Zhong Xiong1, Meng-Kai Ge1, Yun Yu1, Li Xia1, Meng Guo1, Jin-Ke Cheng3, Jun-Ling Liu1,3, Jian-Xiu Yu1,3 & Guo-Qiang Chen1 Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are 1234567890():,; largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers. 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. 2 Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China.
    [Show full text]
  • HNRNPA1 Promotes Recognition of Splice Site Decoys by U2AF2 in Vivo
    Downloaded from genome.cshlp.org on October 10, 2021 - Published by Cold Spring Harbor Laboratory Press Research HNRNPA1 promotes recognition of splice site decoys by U2AF2 in vivo Jonathan M. Howard,1,5 Hai Lin,2,5 Andrew J. Wallace,1 Garam Kim,1 Jolene M. Draper,1 Maximilian Haeussler,3 Sol Katzman,3 Masoud Toloue,4 Yunlong Liu,2 and Jeremy R. Sanford1 1Department of Molecular, Cellular and Developmental Biology, University of California Santa Cruz, Santa Cruz, California 95064, USA; 2Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; 3Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA; 4Bioo Scientific Corporation, Austin, Texas 78744, USA Alternative pre-mRNA splicing plays a major role in expanding the transcript output of human genes. This process is regulated, in part, by the interplay of trans-acting RNA binding proteins (RBPs) with myriad cis-regulatory elements scat- tered throughout pre-mRNAs. These molecular recognition events are critical for defining the protein-coding sequences (exons) within pre-mRNAs and directing spliceosome assembly on noncoding regions (introns). One of the earliest events in this process is recognition of the 3′ splice site (3′ss) by U2 small nuclear RNA auxiliary factor 2 (U2AF2). Splicing reg- ulators, such as the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), influence spliceosome assembly both in vitro and in vivo, but their mechanisms of action remain poorly described on a global scale. HNRNPA1 also promotes proofread- ing of 3′ss sequences though a direct interaction with the U2AF heterodimer.
    [Show full text]
  • Control of Pre-Mrna Splicing by the General Splicing Factors PUF60 and U2AF 65 M Hastings, Eric Allemand, D Duelli, M
    Control of Pre-mRNA Splicing by the General Splicing Factors PUF60 and U2AF 65 M Hastings, Eric Allemand, D Duelli, M. Myers, A. R. Krainer To cite this version: M Hastings, Eric Allemand, D Duelli, M. Myers, A. R. Krainer. Control of Pre-mRNA Splicing by the General Splicing Factors PUF60 and U2AF 65. PLoS ONE, Public Library of Science, 2007, 2 (6), pp.e538. 10.1371/journal.pone.0000538. hal-02462773 HAL Id: hal-02462773 https://hal.archives-ouvertes.fr/hal-02462773 Submitted on 31 Jan 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Control of Pre-mRNA Splicing by the General Splicing Factors PUF60 and U2AF65 Michelle L. Hastings, Eric Allemand¤, Dominik M. Duelli, Michael P. Myers, Adrian R. Krainer* Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America Pre-mRNA splicing is a crucial step in gene expression, and accurate recognition of splice sites is an essential part of this process. Splice sites with weak matches to the consensus sequences are common, though it is not clear how such sites are efficiently utilized. Using an in vitro splicing-complementation approach, we identified PUF60 as a factor that promotes splicing of an intron with a weak 39 splice-site.
    [Show full text]
  • Large-Scale Analysis of Genome and Transcriptome Alterations in Multiple Tumors Unveils Novel Cancer-Relevant Splicing Networks
    Downloaded from genome.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks Endre Sebestyén1,*, Babita Singh1,*, Belén Miñana1,2, Amadís Pagès1, Francesca Mateo3, Miguel Angel Pujana3, Juan Valcárcel1,2,4, Eduardo Eyras1,4,5 1Universitat Pompeu Fabra, Dr. Aiguader 88, E08003 Barcelona, Spain 2Centre for Genomic Regulation, Dr. Aiguader 88, 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, Passeig Lluís Companys 23, E08010 Barcelona, Spain *Equal contribution 5Correspondence to: [email protected] Keywords: alternative splicing, RNA binding proteins, splicing networks, cancer 1 Downloaded from genome.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract 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 systematically 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 alternatively 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 undifferentiated cells.
    [Show full text]
  • The RNA Splicing Response to DNA Damage
    Biomolecules 2015, 5, 2935-2977; doi:10.3390/biom5042935 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Review The RNA Splicing Response to DNA Damage Lulzim Shkreta and Benoit Chabot * Département de Microbiologie et d’Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-819-821-8000 (ext. 75321); Fax: +1-819-820-6831. Academic Editors: Wolf-Dietrich Heyer, Thomas Helleday and Fumio Hanaoka Received: 12 August 2015 / Accepted: 16 October 2015 / Published: 29 October 2015 Abstract: The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post-translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging.
    [Show full text]
  • Discovering Transcription and Splicing Networks in Myelodysplastic Syndromes
    University of Central Florida STARS Faculty Bibliography 2010s Faculty Bibliography 1-1-2013 Discovering Transcription and Splicing Networks in Myelodysplastic Syndromes Hongyan Wang Jianguo Wen Chung-che Chang University of Central Florida Xiaobo Zhou Find similar works at: https://stars.library.ucf.edu/facultybib2010 University of Central Florida Libraries http://library.ucf.edu This Article is brought to you for free and open access by the Faculty Bibliography at STARS. It has been accepted for inclusion in Faculty Bibliography 2010s by an authorized administrator of STARS. For more information, please contact [email protected]. Recommended Citation Wang, Hongyan; Wen, Jianguo; Chang, Chung-che; and Zhou, Xiaobo, "Discovering Transcription and Splicing Networks in Myelodysplastic Syndromes" (2013). Faculty Bibliography 2010s. 4824. https://stars.library.ucf.edu/facultybib2010/4824 Discovering Transcription and Splicing Networks in Myelodysplastic Syndromes Hongyan Wang1, Jianguo Wen2, Chung-che Chang3, Xiaobo Zhou1* 1 Center for Bioinformatics and Systems Biology, Division of Radiologic Sciences, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, United States of America, 2 Department of Pathology, the Methodist Hospital Research Institute, Houston, Texas, United States of America, 3 Department of Pathology, University of Central Florida, Orlando, Florida, United States of America Abstract More and more transcription factors and their motifs have been reported and linked to specific gene expression levels. However, focusing only on transcription is not sufficient for mechanism research. Most genes, especially in eukaryotes, are alternatively spliced to different isoforms. Some of these isoforms increase the biodiversity of proteins. From this viewpoint, transcription and splicing are two of important mechanisms to modulate expression levels of isoforms.
    [Show full text]
  • Wilms' Tumour 1 (WT1) in Development, Homeostasis and Disease
    © 2017. Published by The Company of Biologists Ltd | Development (2017) 144, 2862-2872 doi:10.1242/dev.153163 PRIMER Wilms’ tumour 1 (WT1) in development, homeostasis and disease Nicholas D. Hastie* ABSTRACT particularly those involving mesenchyme-to-epithelial transitions The study of genes mutated in human disease often leads to new (MET) and the reverse process, epithelial-to-mesenchyme transition insights into biology as well as disease mechanisms. One such gene (EMT); (3) the cellular origins of mesenchymal progenitors for a is Wilms’ tumour 1 (WT1), which plays multiple roles in development, variety of tissue types, pinpointing the key role of the mesothelium; tissue homeostasis and disease. In this Primer, I summarise how this and (4) fundamental aspects of transcription and epigenetic multifaceted gene functions in various mammalian tissues and regulation. WT1 is also an example of how protein isoforms organs, including the kidney, gonads, heart and nervous system. differing by just a few amino acids may have profoundly different This is followed by a discussion of our current understanding of the functions. Here, I provide an overview of the WT1 gene, molecular mechanisms by which WT1 and its two major isoforms highlighting how it functions in the development and homeostasis regulate these processes at the transcriptional and post- of various organs and tissues, and how its mutation can lead to transcriptional levels. disease. KEY WORDS: WT1, Developmental disorders, Homeostasis, WT1 structure, evolution and isoforms Molecular mechanisms of disease The mammalian WT1 gene is ∼50 kb in length, encoding proteins from as many as ten exons. There are at least 36 potential Introduction mammalian WT1 isoforms, the diversity created through a The Wilms’ tumour 1 (WT1) gene was first identified in 1990 as a combination of alternative transcription start sites, translation start strong candidate predisposition gene for Wilms’ tumour(Calletal., sites, splicing and RNA editing (Fig.
    [Show full text]
  • Hnrnp A/B Proteins: an Encyclopedic Assessment of Their Roles in Homeostasis and Disease
    biology Review hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease Patricia A. Thibault 1,2 , Aravindhan Ganesan 3, Subha Kalyaanamoorthy 4, Joseph-Patrick W. E. Clarke 1,5,6 , Hannah E. Salapa 1,2 and Michael C. Levin 1,2,5,6,* 1 Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada; [email protected] (P.A.T.); [email protected] (J.-P.W.E.C.); [email protected] (H.E.S.) 2 Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK S7N 0X8, Canada 3 ArGan’s Lab, School of Pharmacy, Faculty of Science, University of Waterloo, Waterloo, ON N2L 3G1, Canada; [email protected] 4 Department of Chemistry, Faculty of Science, University of Waterloo, Waterloo, ON N2L 3G1, Canada; [email protected] 5 Department of Health Sciences, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada 6 Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada * Correspondence: [email protected] Simple Summary: The hnRNP A/B family of proteins (comprised of A1, A2/B1, A3, and A0) contributes to the regulation of the majority of cellular RNAs. Here, we provide a comprehensive overview of what is known of each protein’s functions, highlighting important differences between them. While there is extensive information about A1 and A2/B1, we found that even the basic Citation: Thibault, P.A.; Ganesan, A.; functions of the A0 and A3 proteins have not been well-studied.
    [Show full text]
  • New Roles for the RNA Processing Factors Cfim68 and SRPK2 Highlight Unexpected Links in the Control of Mammalian Gene Expression
    PhD Program in Translational and Molecular Medicine DIMET XXII Cycle, Academic Year 2008-2009 University of Milano-Bicocca School of Medicine and Faculty of Science New roles for the RNA processing factors CFIm68 and SRPK2 highlight unexpected links in the control of mammalian gene expression Silvia Vivarelli – No. 708258 1 2 A mio padre, Agostino 3 4 TABLE OF CONTENTS Chapter 1............................................................................................. 8 GENERAL INTRODUCTION ......................................................... 8 1. The Alternative Splicing .............................................................. 8 1.1 The Alternative Splicing Mechanism..................................... 8 1.2 The Splicing Reaction ............................................................ 9 1.3 Alternative Splicing Regulation ........................................... 13 1.4 The SR Family of Proteins ................................................... 21 1.4.1 SR Proteins: an overview .................................................. 21 1.4.2 SR Proteins: a Vertical Integration of Gene Expression ... 25 1.4.3 SR Protein Kinases............................................................ 26 1.5 Signal Transduction Pathways: from Extracellular Stimuli to Alternative Splicing.................................................................... 29 1.6 Stressful Splicing: the Effects of Paraquat ........................... 30 2. The 3’ End Formation and Export.............................................. 31 2.1 Molecular
    [Show full text]