DOCSLIB.ORG

Temperature Regulates Splicing Efficiency of the Cold-Inducible RNA-Binding Protein Gene Cirbp

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Temperature Regulates Splicing Efficiency of the Cold-Inducible RNA-Binding Protein Gene Cirbp Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Temperature regulates splicing efficiency of the cold-inducible RNA-binding protein gene Cirbp Ivana Gotic,1 Saeed Omidi,2 Fabienne Fleury-Olela,1 Nacho Molina,2,3 Felix Naef,2 and Ueli Schibler1 1Department of Molecular Biology, University of Geneva, CH-1211 Geneva 4, Switzerland; 2The Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland In mammals, body temperature fluctuates diurnally around a mean value of 36°C–37°C. Despite the small differences between minimal and maximal values, body temperature rhythms can drive robust cycles in gene expression in cultured cells and, likely, animals. Here we studied the mechanisms responsible for the temperature- dependent expression of cold-inducible RNA-binding protein (CIRBP). In NIH3T3 fibroblasts exposed to simulated mouse body temperature cycles, Cirbp mRNA oscillates about threefold in abundance, as it does in mouse livers. This daily mRNA accumulation cycle is directly controlled by temperature oscillations and does not depend on the cells’ circadian clocks. Here we show that the temperature-dependent accumulation of Cirbp mRNA is controlled primarily by the regulation of splicing efficiency, defined as the fraction of Cirbp pre-mRNA processed into mature mRNA. As revealed by genome-wide “approach to steady-state” kinetics, this post-transcriptional mechanism is widespread in the temperature-dependent control of gene expression. [Keywords: Cirbp; splicing efficiency; temperature; circadian rhythms] Supplemental material is available for this article. Received July 12, 2016; revised version accepted August 19, 2016. Temperature is a fundamental physical parameter that they must be synchronized by the SCN and/or environ- influences metabolism in all organisms by modulating mental Zeitgebers (timing cues), such as light–dark cy- the rate of biochemical reactions. Endothermic organisms cles, in order to maintain phase coherence and rhythmic like mammals have acquired special thermoregula- physiology in the body. Without a functional SCN, labora- tory adaptation mechanisms in order to decrease their tory rodents kept in constant darkness lose virtually all dependence on environmental temperature. These mech- overt rhythms in behavior and physiology, including anisms maintain core body temperature (CBT) within a CBT cycles (Refinetti et al. 1994). favorable range, allowing efficient metabolic activity While the period length (τ) of circadian oscillations is re- throughout diurnal and seasonal cycles (for review, see markably resilient to temperature variations, a phenome- Tattersall 2012). non called temperature compensation, the phase is Although regulated around a species-specific set point, exquisitely sensitive to temperature perturbations, in par- mammalian CBT shows diurnal oscillations of ∼0.4°C– ticular in peripheral cells. In fact, in cultured fibroblasts 6.0°C (for review, see Refinetti 2010). These regular oscil- and tissue explants, the phase of circadian clock gene ex- lations are generated under the control of the circadian pression can be perfectly synchronized by simulated CBT timekeeping system, which is composed of a master pace- cycles (Brown et al. 2002; Buhr et al. 2010; Saini et al. maker in the brain’s suprachiasmatic nucleus (SCN) and 2012). subsidiary peripheral clocks in nearly all other cells of In intact animals, the systemic synchronization cues the body (Dibner et al. 2010). Although peripheral circadi- governed by the SCN and/or environment also comprise an oscillators are self-sustained and cell-autonomous, feeding–fasting behavior and blood-borne factors (for review, see Schibler et al. 2015). Owing to this com- plexity, it is challenging to assess to what extent CBT rhythms contribute to diurnal gene expression and the 3Present address: Institute of Genetics and Molecular and Cellular Biol- ogy, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67400 Ill- kirch, France Corresponding author: [email protected] © 2016 Gotic et al. This article, published in Genes & Development,is Article published online ahead of print. Article and publication date are available under a Creative Commons License (Attribution 4.0 Internation- online at http://www.genesdev.org/cgi/doi/10.1101/gad.287094.116. al), as described at http://creativecommons.org/licenses/by/4.0/. GENES & DEVELOPMENT 30:1–13 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/16; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Gotic et al. synchronization of peripheral clocks in vivo. Nonethe- is widespread in the control of temperature-dependent less, experiments with mice harboring inactive hepato- gene expression. cyte clocks revealed robust diurnal accumulation cycles for a number of heat- and cold-inducible transcripts. The peak expression of these transcripts at times when CBT Results was maximal and minimal, respectively, suggests that Mild cold exposure increases the expression of a single they are likely driven directly by body temperature oscil- Cirbp mRNA isoform without affecting its pre-mRNA lations (Kornmann et al. 2007). levels The up-regulation of many heat-inducible genes is me- diated by transcriptional mechanisms depending on heat- In various mouse tissues, Cirbp mRNA levels follow a di- shock transcription factors, mostly HSF1, whose mono- urnal pattern, reaching zenith and nadir values when body mers are sequestered into inert cytosolic protein complex- temperature is minimal and maximal, respectively (Sup- es with HSP90 and other proteins at a lower CBT. Upon plemental Fig. S1A,B). Since local circadian oscillators temperature elevation, HSF1 monomers get released, tri- are not required for these oscillations in animals (Korn- merize, translocate into the nucleus, and bind to heat- mann et al. 2007) and since Cirbp mRNA accumulation shock response elements (HSEs) within promoter and en- is known to be temperature-dependent, we considered hancer sequences of their target genes. The circadian core rhythmic Cirbp expression to be likely driven directly clock gene Per2 is among these targets, possibly explain- by CBT cycles. Indeed, simulated CBT rhythms are suffi- ing the contribution of HSF1 to the synchronization of cient to elicit cyclic Cirbp mRNA and protein expression circadian gene expression by simulated CBT rhythms in cultured NIH3T3 fibroblasts (Morf et al. 2012), and we (Reinke et al. 2008; Buhr et al. 2010; Tamaru et al. 2011; therefore used these cells to study the underpinning Saini et al. 2012). mechanisms. In contrast to mouse livers, this model sys- In contrast to the mechanisms governing heat-induced tem allowed us to identify the impact of temperature in gene expression, those involved in cold-induced gene ex- the absence of potential confounding effects caused by cir- pression are still largely elusive. Cirbp, encoding the culating hormones and metabolites. cold-inducible RNA-binding protein CIRBP (also abbrevi- Previous studies have shown that mild cold exposure ated as CIRP), is among the proteins whose accumulation (32°C) increases the concentration of Cirbp mRNA in cul- displays diurnal oscillations that are likely driven by CBT tured cells (Nishiyama et al. 1997). To examine whether rhythms (Nishiyama et al. 1997, 1998; Kornmann et al. the level of Cirbp pre-mRNA transcripts was also changed 2007; Morf et al. 2012). CIRBP was originally described during cold exposure, we performed RNase protection as- as a human UV stress-induced factor, then named A18 says (RPAs). By using an RNA probe that protects the in- hnRNP, involved in the cellular genotoxic stress response tron 6–exon 7 boundary region of Cirbp transcripts from (Fornace et al. 1988; Yang and Carrier 2001). Its tempera- RNase A/T1 digestion, we were able to simultaneously ture-dependent expression became apparent during a quantify the levels of Cirbp pre-mRNA and mRNA spe- PCR-based search for RNA-binding domain-containing cies within a particular sample (Fig. 1A). As shown in Fig- proteins (RBPs) present in mouse testes (Nishiyama ure 1, B and C, cold exposure caused an increase in Cirbp et al. 1997, 1998). CIRBP appears to be an important mod- mRNA but did not affect the level of its precursors. A sim- ulator of proliferation in cellular stress conditions, includ- ilar conclusion was reached for diurnal Cirbp mRNA and ing cancer, where it is thought to exert an activating or pre-mRNA accumulation in mouse livers when we ana- inhibitory role depending on the cell type and the transfor- lyzed published RNA sequencing (RNA-seq) data (Atger mation state of the tumor (Hamid et al. 2003; Masuda et al. 2015). While Cirbp mRNA oscillated in abundance et al. 2012; Ren et al. 2014; Sakurai et al. 2015; Wang with the expected phase, Cirbp pre-mRNA levels re- et al. 2015). mained nearly constant throughout the day (Supplemen- CIRBP is thought to protect bound target RNAs from tal Fig. S1C). degradation, enhance their export and translation in the Next, we asked whether different temperatures induced cytoplasm (Yang and Carrier 2001; Morf et al. 2012), and the expression of specific Cirbp mRNA isoforms by either regulate the choice of alternative polyadenylation sites the use of different transcription start sites
Load more

Recommended publications
  • The Expression of Cold-Inducible RNA-Binding Protein Mrna in Sow Genital Tract Is Modulated by Natural Mating, but Not by Seminal Plasma
    International Journal of Molecular Sciences Article The Expression of Cold-Inducible RNA-Binding Protein mRNA in Sow Genital Tract Is Modulated by Natural Mating, but not by Seminal Plasma Jaume Gardela 1,2 , Mateo Ruiz-Conca 1,2 , Cristina A. Martinez 1 , Dominic Wright 3, Manel López-Béjar 2,4, Heriberto Rodriguez-Martinez 1 and Manuel Alvarez-Rodriguez 1,2,* 1 Department of Biomedical and Clinical Sciences (BKV), Division of Children’s and Women Health (BKH), Obstetrics and Gynaecology, Linköping University, 58185 Linköping, Sweden; [email protected] (J.G.); [email protected] (M.R.-C.); [email protected] (C.A.M.); [email protected] (H.R.-M.) 2 Department of Animal Health and Anatomy, Veterinary Faculty, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; [email protected] or [email protected] 3 Department of Physics, Chemistry and Biology, Faculty of Science and Engineering, Linköping University, 58185 Linköping, Sweden; [email protected] 4 College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA * Correspondence: [email protected]; Tel.: +46-(0)729427883 Received: 10 June 2020; Accepted: 24 July 2020; Published: 27 July 2020 Abstract: The RNA-binding proteins (RBPs), some of them induced by transient receptor potential (TRP) ion channels, are crucial regulators of RNA function that can contribute to reproductive pathogenesis, including inflammation and immune dysfunction. This study aimed to reveal the influence of spermatozoa, seminal plasma, or natural mating on mRNA expression of RBPs and TRP ion channels in different segments of the internal genital tract of oestrous, preovulatory sows.
    [Show full text]
  • A Comparative Analysis of Transcribed Genes in the Mouse Hypothalamus and Neocortex Reveals Chromosomal Clustering
    A comparative analysis of transcribed genes in the mouse hypothalamus and neocortex reveals chromosomal clustering Wee-Ming Boon*, Tim Beissbarth†, Lavinia Hyde†, Gordon Smyth†, Jenny Gunnersen*, Derek A. Denton*‡, Hamish Scott†, and Seong-Seng Tan* *Howard Florey Institute, University of Melbourne, Parkville 3052, Australia; and †Genetics and Bioinfomatics Division, Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville 3050, Australia Contributed by Derek A. Denton, August 26, 2004 The hypothalamus and neocortex are subdivisions of the mamma- representing all of the genes that are expressed (qualitative and lian forebrain, and yet, they have vastly different evolutionary quantitative) in the hypothalamus and neocortex under standard histories, cytoarchitecture, and biological functions. In an attempt conditions. to define these attributes in terms of their genetic activity, we have In the current study, we describe the use of the Serial Analysis compared their genetic repertoires by using the Serial Analysis of of Gene Expression (SAGE) database, which allows simulta- Gene Expression database. From a comparison of 78,784 hypothal- neous detection of the expression levels of the entire genome amus tags with 125,296 neocortical tags, we demonstrate that each without a priori knowledge of gene sequences (13). SAGE takes structure possesses a different transcriptional profile in terms of advantage of the fact that a small sequence tag taken from a gene ontological characteristics and expression levels. Despite its defined position within the transcript is sufficient to identify the more recent evolutionary history, the neocortex has a more com- gene (from known cDNA or EST sequences), and up to 40 tags plex pattern of gene activity.
    [Show full text]
  • An Annual Cycle of Gene Regulation in the Red-Legged Salamander Mental Gland: from Hypertrophy to Expression of Rapidly Evolving Pheromones
    bioRxiv preprint doi: https://doi.org/10.1101/261495; this version posted February 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. An annual cycle of gene regulation in the red-legged salamander mental gland: from hypertrophy to expression of rapidly evolving pheromones Damien B. Wilburn1,2§ and Richard C. Feldhoff1 1Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292 2Department of Genome Sciences, University of Washington, Seattle, WA 98195 §Corresponding author Email addresses: DBW: [email protected] RCF: [email protected] - 1 - bioRxiv preprint doi: https://doi.org/10.1101/261495; this version posted February 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Cell differentiation is mediated by synchronized waves of coordinated expression for hundreds to thousands of genes, and must be an exquisitely regulated process to produce complex tissues and phenotypes. For many animal species, sexual selection has driven the development of elaborate male ornaments, requiring sex-specific differentiation pathways. One such male ornament is the pheromone-producing mental gland of the red-legged salamander (Plethodon shermani). Mental gland development follows an annual cycle of extreme hypertrophy, production of pheromones for the ~2 month mating season, and then complete resorption before repeating the process in the following year.
    [Show full text]
  • Human CIRBP (1-172, His-Tag) - Purified
    OriGene Technologies, Inc. OriGene Technologies GmbH 9620 Medical Center Drive, Ste 200 Schillerstr. 5 Rockville, MD 20850 32052 Herford UNITED STATES GERMANY Phone: +1-888-267-4436 Phone: +49-5221-34606-0 Fax: +1-301-340-8606 Fax: +49-5221-34606-11 [email protected] [email protected] AR09973PU-N Human CIRBP (1-172, His-tag) - Purified Alternate names: A18HNRNP, CIRP, Cold-inducible RNA-binding protein, Glycine-rich RNA-binding protein CIRP Quantity: 0.1 mg Concentration: 0.5 mg/ml (determined by Bradford assay) Background: Cold inducible RNA-binding protein, also known as CIRBP, plays a protective role in the genotoxic stress response by stabilizing transcripts of genes involved in cell survival. It is localizes to the nucleus and contains one RRM (RNA recognition motif) domain. Expressed ubiquitously, CIRBP is thought to play an essential role in the suppression of cellular proliferation in response to UV irradiation or extreme cold. Uniprot ID: Q14011 NCBI: NP_001271 GeneID: 1153 Species: Human Source: E. coli Format: State: Liquid purified protein Purity: >95% by SDS-PAGE Buffer System: 20mM Tris-HCl buffer (pH 8.0) containing 1mM DTT, 50% glycerol, 0.2M NaCl Description: Recombinant human CIRBP protein, fused to His-tag at N-terminus, was expressed in E.coli and purified by using conventional chromatography techniques. AA Sequence: MGSSHHHHHH SSGLVPRGSH MASDEGKLFV GGLSFDTNEQ SLEQVFSKYG QISEVVVVKD RETQRSRGFG FVTFENIDDA KDAMMAMNGK SVDGRQIRVD QAGKSSDNRS RGYRGGSAGG RGFFRGGRGR GRGFSRGGGD RGYGGNRFES RSGGYGGSRD YYSSRSQSGG YSDRSSGGSY RDSYDSYATH NE Molecular weight: 20.8 kDa (192aa) confirmed by MALDI-TOF Storage: Store undiluted at 2-8°C for up to two weeks or (in aliquots) at -20°C or -70°C for longer.
    [Show full text]
  • CIRBP Polyclonal Antibody
    PRODUCT DATA SHEET Bioworld Technology,Inc. CIRBP polyclonal antibody Catalog: BS6943 Host: Rabbit Reactivity: Human,Mouse,Rat BackGround: by affinity-chromatography using epitope-specific im- CIRP, also known as CIRBP (cold inducible RNA binding munogen and the purity is > 95% (by SDS-PAGE). protein) or A18HNRNP, is a 172 amino acid protein that Applications: localizes to the nucleus and contains one RRM (RNA WB: 1:500~1:2000 recognition motif) domain. Expressed ubiquitously, CIRP IHC: 1:50~1:200 is thought to play an essential role in the suppression of Storage&Stability: cellular proliferation in response to UV irradiation or ex- Store at 4°C short term. Aliquot and store at -20°C long treme cold. Human CIRP, which may be involved in the term. Avoid freeze-thaw cycles. pathogenesis of endometrial carcinoma, shares 95% se- Specificity: quence identity with its mouse counterpart, suggesting a CIRBP polyclonal antibody detects endogenous levels of conserved role between species. The gene encoding CIRP CIRBP protein. maps to human chromosome 19, which is the genetic DATA: home for a number of immunoglobulin superfamily members, including the killer cell and leukocyte Ig-like receptors, a number of ICAMs, the CEACAM and PSG family and Fc receptors (FcRs). Product: Rabbit IgG, 1mg/ml in PBS with 0.02% sodium azide, 50% glycerol, pH7.2 Molecular Weight: WesternBlot (WB) analysis of CIRBP polyclonal antibody ~ 19 kDa Note: Swiss-Prot: For research use only, not for use in diagnostic procedure. Q14011 Purification&Purity: The antibody was affinity-purified from rabbit antiserum Bioworld Technology, Inc. Bioworld technology, co. Ltd.
    [Show full text]
  • Variation in Protein Coding Genes Identifies Information Flow
    bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 1 1 2 3 4 5 Variation in protein coding genes identifies information flow as a contributor to 6 animal complexity 7 8 Jack Dean, Daniela Lopes Cardoso and Colin Sharpe* 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Institute of Biological and Biomedical Sciences 25 School of Biological Science 26 University of Portsmouth, 27 Portsmouth, UK 28 PO16 7YH 29 30 * Author for correspondence 31 [email protected] 32 33 Orcid numbers: 34 DLC: 0000-0003-2683-1745 35 CS: 0000-0002-5022-0840 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Abstract bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 2 1 Across the metazoans there is a trend towards greater organismal complexity. How 2 complexity is generated, however, is uncertain. Since C.elegans and humans have 3 approximately the same number of genes, the explanation will depend on how genes are 4 used, rather than their absolute number.
    [Show full text]
  • Developing Specific Molecular Biomarkers for Thermal Stress In
    Akbarzadeh et al. BMC Genomics (2018) 19:749 https://doi.org/10.1186/s12864-018-5108-9 RESEARCHARTICLE Open Access Developing specific molecular biomarkers for thermal stress in salmonids Arash Akbarzadeh1,2* , Oliver P Günther3, Aimee Lee Houde1, Shaorong Li1, Tobi J Ming1, Kenneth M Jeffries4, Scott G Hinch5 and Kristina M Miller1 Abstract Background: Pacific salmon (Oncorhynchus spp.) serve as good biological indicators of the breadth of climate warming effects on fish because their anadromous life cycle exposes them to environmental challenges in both marine and freshwater environments. Our study sought to mine the extensive functional genomic studies in fishes to identify robust thermally-responsive biomarkers that could monitor molecular physiological signatures of chronic thermal stress in fish using non-lethal sampling of gill tissue. Results: Candidate thermal stress biomarkers for gill tissue were identified using comparisons among microarray datasets produced in the Molecular Genetics Laboratory, Pacific Biological Station, Nanaimo, BC, six external, published microarray studies on chronic and acute temperature stress in salmon, and a comparison of significant genes across published studies in multiple fishes using deep literature mining. Eighty-two microarray features related to 39 unique gene IDs were selected as candidate chronic thermal stress biomarkers. Most of these genes were identified both in the meta-analysis of salmon microarray data and in the literature mining for thermal stress markers in salmonids and other fishes. Quantitative reverse transcription PCR (qRT-PCR) assays for 32 unique genes with good efficiencies across salmon species were developed, and their activity in response to thermally challenged sockeye salmon (O. nerka)and Chinook salmon (O.
    [Show full text]
  • A Novel Candidate Gene for Temperature-Dependent Sex Determination in the Common Snapping Turtle
    | GENETICS OF SEX A Novel Candidate Gene for Temperature-Dependent Sex Determination in the Common Snapping Turtle Anthony L. Schroeder,*,1 Kelsey J. Metzger,† Alexandra Miller,* and Turk Rhen*,2 *Department of Biology, University of North Dakota, Grand Forks, North Dakota 58202, and †Center for Learning Innovation, University of Minnesota, Rochester, Minnesota 55904 ABSTRACT Temperature-dependent sex determination (TSD) was described nearly 50 years ago. Researchers have since identified many genes that display differential expression at male- vs. female-producing temperatures. Yet, it is unclear whether these genes (1) are involved in sex determination per se, (2) are downstream effectors involved in differentiation of ovaries and testes, or (3) are thermo-sensitive but unrelated to gonad development. Here we present multiple lines of evidence linking CIRBP to sex determination in the snapping turtle, Chelydra serpentina. We demonstrate significant associations between a single nucleotide polymorphism (SNP) (c63A . C) in CIRBP, transcript levels in embryonic gonads during specification of gonad fate, and sex in hatchlings from a thermal regime that produces mixed sex ratios. The A allele was induced in embryos exposed to a female-producing temperature, while expression of the C allele did not differ between female- and male-producing temperatures. In accord with this pattern of temperature- dependent, allele-specific expression, AA homozygotes were more likely to develop ovaries than AC heterozygotes, which, in turn, were more likely to develop ovaries than CC homozygotes. Multiple regression using SNPs in CIRBP and adjacent loci suggests that c63A . C may be the causal variant or closely linked to it. Differences in CIRBP allele frequencies among turtles from northern Minnesota, southern Minnesota, and Texas reflect small and large-scale latitudinal differences in TSD pattern.
    [Show full text]
  • (NF1) As a Breast Cancer Driver
    INVESTIGATION Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver Marsha D. Wallace,*,† Adam D. Pfefferle,‡,§,1 Lishuang Shen,*,1 Adrian J. McNairn,* Ethan G. Cerami,** Barbara L. Fallon,* Vera D. Rinaldi,* Teresa L. Southard,*,†† Charles M. Perou,‡,§,‡‡ and John C. Schimenti*,†,§§,2 *Department of Biomedical Sciences, †Department of Molecular Biology and Genetics, ††Section of Anatomic Pathology, and §§Center for Vertebrate Genomics, Cornell University, Ithaca, New York 14853, ‡Department of Pathology and Laboratory Medicine, §Lineberger Comprehensive Cancer Center, and ‡‡Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27514, and **Memorial Sloan-Kettering Cancer Center, New York, New York 10065 ABSTRACT Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity. Relevant mouse models are powerful for untangling this problem because such heterogeneity can be controlled. Inbred Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors that have tumor gene expression profiles closely resembling mature human mammary luminal cell signatures. We genomically characterized mammary adenocarcinomas from these mice to identify cancer-causing genomic events that overlap common alterations in human breast cancer. Chaos3 tumors underwent recurrent copy number alterations (CNAs), particularly deletion of the RAS inhibitor Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs including NF1, which is deleted or mutated in 27.7% of all breast carcinomas. Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity to RAS pathway inhibitors. These results indicate that spontaneous NF1 loss can drive breast cancer. This should be informative for treatment of the significant fraction of patients whose tumors bear NF1 mutations.
    [Show full text]
  • Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
    Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein
    [Show full text]
  • An Integrative Genomic Analysis of the Longshanks Selection Experiment for Longer Limbs in Mice
    bioRxiv preprint doi: https://doi.org/10.1101/378711; this version posted August 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: 2 An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice 3 Short Title: 4 Genomic response to selection for longer limbs 5 One-sentence summary: 6 Genome sequencing of mice selected for longer limbs reveals that rapid selection response is 7 due to both discrete loci and polygenic adaptation 8 Authors: 9 João P. L. Castro 1,*, Michelle N. Yancoskie 1,*, Marta Marchini 2, Stefanie Belohlavy 3, Marek 10 Kučka 1, William H. Beluch 1, Ronald Naumann 4, Isabella Skuplik 2, John Cobb 2, Nick H. 11 Barton 3, Campbell Rolian2,†, Yingguang Frank Chan 1,† 12 Affiliations: 13 1. Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany 14 2. University of Calgary, Calgary AB, Canada 15 3. IST Austria, Klosterneuburg, Austria 16 4. Max Planck Institute for Cell Biology and Genetics, Dresden, Germany 17 Corresponding author: 18 Campbell Rolian 19 Yingguang Frank Chan 20 * indicates equal contribution 21 † indicates equal contribution 22 Abstract: 23 Evolutionary studies are often limited by missing data that are critical to understanding the 24 history of selection. Selection experiments, which reproduce rapid evolution under controlled 25 conditions, are excellent tools to study how genomes evolve under strong selection. Here we 1 bioRxiv preprint doi: https://doi.org/10.1101/378711; this version posted August 19, 2018.
    [Show full text]
  • Temperature Regulates Splicing Efficiency of the Cold-Inducible RNA-Binding Protein Gene Cirbp
    Downloaded from genesdev.cshlp.org on May 19, 2020 - Published by Cold Spring Harbor Laboratory Press Temperature regulates splicing efficiency of the cold-inducible RNA-binding protein gene Cirbp Ivana Gotic,1 Saeed Omidi,2 Fabienne Fleury-Olela,1 Nacho Molina,2,3 Felix Naef,2 and Ueli Schibler1 1Department of Molecular Biology, University of Geneva, CH-1211 Geneva 4, Switzerland; 2The Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland In mammals, body temperature fluctuates diurnally around a mean value of 36°C–37°C. Despite the small differences between minimal and maximal values, body temperature rhythms can drive robust cycles in gene expression in cultured cells and, likely, animals. Here we studied the mechanisms responsible for the temperature- dependent expression of cold-inducible RNA-binding protein (CIRBP). In NIH3T3 fibroblasts exposed to simulated mouse body temperature cycles, Cirbp mRNA oscillates about threefold in abundance, as it does in mouse livers. This daily mRNA accumulation cycle is directly controlled by temperature oscillations and does not depend on the cells’ circadian clocks. Here we show that the temperature-dependent accumulation of Cirbp mRNA is controlled primarily by the regulation of splicing efficiency, defined as the fraction of Cirbp pre-mRNA processed into mature mRNA. As revealed by genome-wide “approach to steady-state” kinetics, this post-transcriptional mechanism is widespread in the temperature-dependent control of gene expression. [Keywords: Cirbp; splicing efficiency; temperature; circadian rhythms] Supplemental material is available for this article. Received July 12, 2016; revised version accepted August 19, 2016.
    [Show full text]