DOCSLIB.ORG

Genes for Human General Transcription Initiation Factors TFIIIB

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genes for Human General Transcription Initiation Factors TFIIIB Oncogene (2001) 20, 4877 ± 4883 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Genes for human general transcription initiation factors TFIIIB, TFIIIB- associated proteins, TFIIIC2 and PTF/SNAPC: functional and positional candidates for tumour predisposition or inherited genetic diseases? Michele Purrello*,1, Cinzia Di Pietro1, Antonella Rapisarda1, Valentina Amico1, Veronica Giunta1, Hartmut Engel2, Sean Stevens3, Yng-ju Hsieh3, Martin Teichman3, Zhengxin Wang3, Giovanni Sichel1, Robert Roeder3 and Karl-Heinz Grzeschik2 1Dipartimento di Scienze Biomediche, Sezione di Biologia generale, cellulare e di Genetica molecolare, UniversitaÁ di Catania, 95124 Catania, Italy; 2Zentrum fuÈr Humangenetik, Philipps UniversitaÈt, 35037 Marburg, Germany; 3Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10021, USA TFIIIB, TFIIIC2, and PTF/SNAPC are heteromulti- of gene expression; cell proliferation, dierentiation meric general transcription factors (GTFs) needed for and apoptosis expression of genes encoding small cytoplasmic (scRNAs) and small nuclear RNAs (snRNAs). Their activity is stimulated by viral oncogenes, such as SV40 large T antigen and Adenovirus E1A, and is repressed by Proliferation, dierentiation and apoptosis are the speci®c transcription factors (STFs) acting as anti- result of signi®cant modi®cations of the cell phenotype, oncogenes, such as p53 and pRb. GTFs role as ®nal both at the RNA and the protein level. These targets of critical signal transduction pathways, that phenomena are brought about by speci®c transcription control cell proliferation and dierentiation, and their factors (STFs), that modulate them either positively or involvement in gene expression regulation suggest that negatively. The level of PolIII activity, needed for the the genes encoding them are potential proto-oncogenes or synthesis of 45S rRNA, 5S rRNA, tRNAs, other anti-oncogenes or may be otherwise involved in the scRNAs and snRNAs, is strictly regulated according to pathogenesis of inherited genetic diseases. To test our cell cycle, dierentiation, developmental stage and hypothesis through the positional candidate gene ap- neoplastic status (reviewed by White, 1998). A critical proach, we have determined the physical localization in role is performed by TFIIIB, TFIIIC2 and PTF/ the human genome of the 11 genes, encoding the subunits SNAPC, three general transcription factors (GTFs) of these GTFs, and of three genes for proteins associated that allow the polymerase to interact with promoter with TFIIIB (GTF3BAPs). Our data, obtained by DNA and are essential for the expression of growth- chromosomal in situ hybridization, radiation hybrids related scRNAs and snRNAs (reviewed by Henry et and somatic cell hybrids analysis, demonstrate that these al., 1998; Kumar et al., 1998; Paule and White, 2000). genes are present in the human genome as single copy TFIIIB, TFIIIC2 and PTF/SNAPC are repressed by sequences and that some cluster to the same cytogenetic p53 and pRb, two STFs that negatively control band, alone or in combination with class II GTFs. proliferation and block cells with potentially dangerous Intriguingly, some of them are localized within chromo- mutations from completing the cycle, eventually somal regions where recurrent, cytogenetically detectable activating the apoptotic process (Chu et al., 1997; mutations are seen in speci®c neoplasias, such as Cairns and White, 1998). This inhibition may be neuroblastoma, uterine leyomioma, mucoepidermoid reversed by viruses such as SV40, Hepatitis B virus carcinoma of the salivary glands and hemangioperi- and human T cell leukemia virus type 1 (White, 1998). cytoma, or where mutations causing inherited genetic SV40 large T Antigen, as well as serum stimulation or diseases map, such as Peutz-Jeghers syndrome. Their adenovirus infection, increase the amount of the molecular function and genomic position make these 110 kDa subunit of TFIIIC2, thereby activating the GTF genes interesting candidates for causal involvement factor and, accordingly, PolIII transcription (Sinn et in oncogenesis or in the pathogenesis of inherited genetic al., 1995; Damania et al., 1998; Larminie et al., 1999). diseases. Oncogene (2001) 20, 4877 ± 4883. All TFIIIC2 subunits are overexpressed in ovarian tumours, a leading cause of gynecological cancer Keywords: Cancer Genome Anatomy Project; onco- deaths in the USA (Winter et al., 2000). Finally, genesis; human general transcription factors; regulation expression of the TAF3B2 gene, encoding TFIIIB-90 (Table 1), has been shown to decrease during dierentiation of F9 cells concomitantly with TFIIIB activity (Alzuherri and White, 1998). *Correspondence: M Purrello, E-mail: [email protected] Received 16 November 2000; revised 3 May 2001; accepted 9 May These data strongly suggest that the genes encoding 2001 TFIIIB, TFIIIC2 and PTF/SNAPC are themselves GTFs and oncogenesis M Purrello et al 4878 amongst the ®nal targets of signal transduction path- mutants that interfere with protein-DNA or protein ± ways important for the control of cell proliferation and protein interactions, such as those with upstream dierentiation. In light of their critical metabolic role, regulators like p53 and pRb, might impair the proper mutations eliminating completely the activity of these response to external factors: thus, by in¯uencing PolIII GTFs might be lethal. However, transcription factor associated transcription they might generate in humans pathologic phenotypes, in particular malignancies or other genetic diseases with dysregulation of cellular growth or dierentiation. Table 1 cDNAs used as probes cDNA Locusa References hTFIIIB-150 TAF3B1 Teichmann et al. (2000) Genomics of TFIIIB, GTF3BAPS, TFIIIC2 and PTF/SNAPC hTFIIIB-90 TAF3B2 Wang and Roeder (1995) hGTF3BAP -134 GTF3BAP1 Hsieh et al. (unpublished) To establish the genes encoding the subunits of TFIIIB, TFIIIC2, PTF/SNAPC, and of the three polypeptides hGTF3BAP -120 GTF3BAP2 Hsieh et al. (unpublished) associated with TFIIIB (GTF3BAPs) as positional candidates for tumours and other genetic diseases, we hGTF3BAP -80 GTF3BAP3 Hsieh et al. (unpublished) have determined their genomic localization by in situ rTFIIIC2-220 GTF3C1 Lagna et al. (1994) hybridization, radiation hybrids and human/murine somatic cell hybrids analysis. Southern analysis of hTFIIIC2-110 GTF3C2 Sinn et al. (1995) hybrid cell lines with the cDNA inserts, listed in Table 1, demonstrated that these GTF genes are present in hTFIIIC2-102 GTF3C3 Hsieh et al. (1999a) the human genome as single copy sequences and hTFIIIC2-90 GTF3C4 Hsieh et al. (1999b) allowed the chromosomal assignment of the corre- sponding loci to speci®c human chromosomes (data not hTFIIIC2-63 GTF3C5 Hsieh et al. (1999a) shown). These data were con®rmed and the genomic position of GTF loci was precisely identi®ed through hPTF a SNAPC4 Yoon and Roeder (unpublished) FISH to normal human metaphase and prometaphase hPTF b SNAPC3 Bai et al. (1996) chromosomes (Table 2 and Figure 1). The GTF3C4 locus was physically localized at 9q34 by segregation hPTF g SNAPC1 Yoon and Roeder (1996) analysis of gene-speci®c markers, performed by ampli- hPTF d SNAPC2 Yoon and Roeder (1996) ®cation of clone DNAs from the GeneBridge 4 human radiation hybrid panel (Tables 3 and 4). For groups of aSymbols were assigned by HUGO Nomenclature Committee GTFs mapping at 9q34 and 19p13, analysis of the same Table 2 FISH localization of human genes encoding hGTFs Total number of Total number of Total number of Total number of Number of specific hybridization metaphases hybridization hybridization sites/ specific hybridization sites/total number of Genomic Locus analysed sites metaphase sites hybridization sites position TAF3B1 123 157 1.2 115 73% 5q13 TAF3B2 113 240 2.1 111 46% 14q32 GTF3BAP1 70 127 1.8 70 55% 1p32 GTF3BAP2 109 179 1.6 90 50% 19p13.3 GTF3BAP3 68 118 1.7 66 56% 19q13.3 GTF3C1 46 114 2.5 22 19% 16p11.2 GTF3C2 50 130 2.6 27 21% 2p23 GTF3C3 122 226 1.8 60 26% 2q31 GTF3C5 128 227 1.8 51 22% 9q34 SNAPC1 72 111 1.5 59 53% 14q24.1 SNAPC2 76 59 0.8 48 80% 19p13.3 SNAPC3 87 101 1.2 74 73% 9p23 SNAPC4 63 70 1.1 64 91% 9q34.3 Oncogene GTFs and oncogenesis M Purrello et al 4879 Figure 1 Fluorescence in situ hybridization to normal human chromosomes of cDNA inserts for TAF3B2 (panel A), GTF3C3 (panel B), and SNAPC4 (panel C) demonstrates that they are localized at 14q32, 2q31, 9q34.3, respectively. For each locus a metaphase after FISH and after Giemsa staining is shown, next to an ideogram of the chromosome where the gene is located, as shown by the arrow. Southern and Northern analysis and in situ hybridisation were performed as described (Purrello et al., 1998), by using as probes the cDNA inserts listed in Table 1 radiation hybrids was performed in order to determine hybridization to 1p32 and 19q13.3, respectively (Table the most likely linear order of loci within each cluster. 2). We decided to conclusively con®rm their genomic We included in our RH analysis also GTF2F1, which position by analysing the GeneBridge 4 panel (Table 5), encodes the large 74 kDa subunit of TFIIF (a class II since both chromosomal regions are frequently in- GTF) and which we had previously mapped by FISH volved in structural mutations detected in cells from to chromosome 19p13.3 (Purrello et al., 1995). The dierent neoplasias (Table 6). linear order of GTF genes localized at 9q34 is (centr, The results of the analysis of human/murine hybrid GTF3C5, GTF3C4,
Load more

Recommended publications
  • FK506-Binding Protein 12.6/1B, a Negative Regulator of [Ca2+], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. A link to any extended data will be provided when the final version is posted online. Research Articles: Neurobiology of Disease FK506-Binding Protein 12.6/1b, a negative regulator of [Ca2+], rescues memory and restores genomic regulation in the hippocampus of aging rats John C. Gant1, Eric M. Blalock1, Kuey-Chu Chen1, Inga Kadish2, Olivier Thibault1, Nada M. Porter1 and Philip W. Landfield1 1Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY 40536 2Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294 DOI: 10.1523/JNEUROSCI.2234-17.2017 Received: 7 August 2017 Revised: 10 October 2017 Accepted: 24 November 2017 Published: 18 December 2017 Author contributions: J.C.G. and P.W.L. designed research; J.C.G., E.M.B., K.-c.C., and I.K. performed research; J.C.G., E.M.B., K.-c.C., I.K., and P.W.L. analyzed data; J.C.G., E.M.B., O.T., N.M.P., and P.W.L. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. NIH grants AG004542, AG033649, AG052050, AG037868 and McAlpine Foundation for Neuroscience Research Corresponding author: Philip W. Landfield, [email protected], Department of Pharmacology & Nutritional Sciences, University of Kentucky, 800 Rose Street, UKMC MS 307, Lexington, KY 40536 Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2234-17.2017 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published.
    [Show full text]
  • PARSANA-DISSERTATION-2020.Pdf
    DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks.
    [Show full text]
  • BMC Genomics Biomed Central
    BMC Genomics BioMed Central Research article Open Access The functional modulation of epigenetic regulators by alternative splicing Sergio Lois1,2, Noemí Blanco1,2, Marian Martínez-Balbás*1,2 and Xavier de la Cruz*2,3 Address: 1Instituto de Biología Molecular de Barcelona. CID. Consejo Superior de Investigaciones Científicas (CSIC); 08028 Barcelona, Spain, 2Institut de Recerca Biomèdica-PCB; 08028 Barcelona, Spain and 3Institució Catalana de Recerca i Estudis Avançats (ICREA); Barcelona, Spain Email: Sergio Lois - [email protected]; Noemí Blanco - [email protected]; Marian Martínez-Balbás* - [email protected]; Xavier de la Cruz* - [email protected] * Corresponding authors Published: 25 July 2007 Received: 24 April 2007 Accepted: 25 July 2007 BMC Genomics 2007, 8:252 doi:10.1186/1471-2164-8-252 This article is available from: http://www.biomedcentral.com/1471-2164/8/252 © 2007 Lois et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Epigenetic regulators (histone acetyltransferases, methyltransferases, chromatin- remodelling enzymes, etc) play a fundamental role in the control of gene expression by modifying the local state of chromatin. However, due to their recent discovery, little is yet known about their own regulation. This paper addresses this point, focusing on alternative splicing regulation, a mechanism already known to play an important role in other protein families, e.g. transcription factors, membrane receptors, etc.
    [Show full text]
  • Supplemental Table 1 Enriched Genes in Cortical Astrocytes from Aged
    Supplemental Table 1 Enriched genes in cortical astrocytes from aged and young-adult mice * Genes were present in the astrocyte module from the WGCNA analysis, and contains astrocyte enriched genes compared to microglia and oligodendrocytes # = Fold change of aged astrocyte expression over the average expression of all analyzed samples (microglia, astrocytes: young, old, with and without myelin contamination) $ ; aged = genes only present in the aged astrocyte top 1000 list (used to compare with lists from Cahoy, Lovatt, Doyle; see Fig. 4B), all = genes present in all astrocyte top 1000 lists Gene Symbol* Aged astr. (log2) Young astr.(log2) FC (aged/ aver.)# Location Ptprz1 15.37 15.02 18.76 Plasma Membrane Slc7a10 14.49 14.44 18.28 Plasma Membrane Gjb6 15.13 14.42 18.18 Plasma Membrane Dclk1 14.63 14.28 17.18 unknown Hes5 15.69 15.55 16.94 Nucleus Fgfr3 15.27 14.46 16.54 Plasma Membrane Entpd2 13.85 13.56 15.92 Cytoplasm Grin2c 14.93 14.87 15.75 Plasma Membrane Slc1a2 15.51 15.39 15.58 Plasma Membrane Fjx1 14.36 13.98 14.52 Extracellular Space Slc6a1 14.20 14.16 14.47 Plasma Membrane Kcnk1 12.93 13.49 14.43 Plasma Membrane Ppap2b 16.16 16.10 14.37 Plasma Membrane Fam20a 14.48 14.72 14.00 Extracellular Space Dbx2 13.68 13.32 13.99 Nucleus Itih3 13.93 13.93 13.94 Extracellular Space Htra1 17.12 16.91 13.92 Extracellular Space Atp1a2 14.59 14.48 13.73 Plasma Membrane Scg3 15.71 15.72 13.68 Extracellular Space F3 15.59 15.08 13.51 Plasma Membrane Mmd2 14.22 14.60 13.50 unknown Nrcam 13.73 13.88 13.47 Plasma Membrane Cldn10a 13.37 13.57 13.46
    [Show full text]
  • New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology
    Cancer Research and Treatment 2003;35(4):304-313 New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology Yong-Wan Kim, Ph.D.1, Min-Je Suh, M.S.1, Jin-Sik Bae, M.S.1, Su Mi Bae, M.S.1, Joo Hee Yoon, M.D.2, Soo Young Hur, M.D.2, Jae Hoon Kim, M.D.2, Duck Young Ro, M.D.2, Joon Mo Lee, M.D.2, Sung Eun Namkoong, M.D.2, Chong Kook Kim, Ph.D.3 and Woong Shick Ahn, M.D.2 1Catholic Research Institutes of Medical Science, 2Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul; 3College of Pharmacy, Seoul National University, Seoul, Korea Purpose: This study utilized both mRNA differential significant genes of unknown function affected by the display and the Gene Ontology (GO) analysis to char- HPV-16-derived pathway. The GO analysis suggested that acterize the multiple interactions of a number of genes the cervical cancer cells underwent repression of the with gene expression profiles involved in the HPV-16- cancer-specific cell adhesive properties. Also, genes induced cervical carcinogenesis. belonging to DNA metabolism, such as DNA repair and Materials and Methods: mRNA differential displays, replication, were strongly down-regulated, whereas sig- with HPV-16 positive cervical cancer cell line (SiHa), and nificant increases were shown in the protein degradation normal human keratinocyte cell line (HaCaT) as a con- and synthesis. trol, were used. Each human gene has several biological Conclusion: The GO analysis can overcome the com- functions in the Gene Ontology; therefore, several func- plexity of the gene expression profile of the HPV-16- tions of each gene were chosen to establish a powerful associated pathway, identify several cancer-specific cel- cervical carcinogenesis pathway.
    [Show full text]
  • Genetic Basis of Simple and Complex Traits with Relevance to Avian Evolution
    Genetic basis of simple and complex traits with relevance to avian evolution Małgorzata Anna Gazda Doctoral Program in Biodiversity, Genetics and Evolution D Faculdade de Ciências da Universidade do Porto 2019 Supervisor Miguel Jorge Pinto Carneiro, Auxiliary Researcher, CIBIO/InBIO, Laboratório Associado, Universidade do Porto Co-supervisor Ricardo Lopes, CIBIO/InBIO Leif Andersson, Uppsala University FCUP Genetic basis of avian traits Nota Previa Na elaboração desta tese, e nos termos do número 2 do Artigo 4º do Regulamento Geral dos Terceiros Ciclos de Estudos da Universidade do Porto e do Artigo 31º do D.L.74/2006, de 24 de Março, com a nova redação introduzida pelo D.L. 230/2009, de 14 de Setembro, foi efetuado o aproveitamento total de um conjunto coerente de trabalhos de investigação já publicados ou submetidos para publicação em revistas internacionais indexadas e com arbitragem científica, os quais integram alguns dos capítulos da presente tese. Tendo em conta que os referidos trabalhos foram realizados com a colaboração de outros autores, o candidato esclarece que, em todos eles, participou ativamente na sua conceção, na obtenção, análise e discussão de resultados, bem como na elaboração da sua forma publicada. Este trabalho foi apoiado pela Fundação para a Ciência e Tecnologia (FCT) através da atribuição de uma bolsa de doutoramento (PD/BD/114042/2015) no âmbito do programa doutoral em Biodiversidade, Genética e Evolução (BIODIV). 2 FCUP Genetic basis of avian traits Acknowledgements Firstly, I would like to thank to my all supervisors Miguel Carneiro, Ricardo Lopes and Leif Andersson, for the demanding task of supervising myself last four years.
    [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]
  • Distinguishing Pleiotropy from Linked QTL Between Milk Production Traits
    Cai et al. Genet Sel Evol (2020) 52:19 https://doi.org/10.1186/s12711-020-00538-6 Genetics Selection Evolution RESEARCH ARTICLE Open Access Distinguishing pleiotropy from linked QTL between milk production traits and mastitis resistance in Nordic Holstein cattle Zexi Cai1*†, Magdalena Dusza2†, Bernt Guldbrandtsen1, Mogens Sandø Lund1 and Goutam Sahana1 Abstract Background: Production and health traits are central in cattle breeding. Advances in next-generation sequencing technologies and genotype imputation have increased the resolution of gene mapping based on genome-wide association studies (GWAS). Thus, numerous candidate genes that afect milk yield, milk composition, and mastitis resistance in dairy cattle are reported in the literature. Efect-bearing variants often afect multiple traits. Because the detection of overlapping quantitative trait loci (QTL) regions from single-trait GWAS is too inaccurate and subjective, multi-trait analysis is a better approach to detect pleiotropic efects of variants in candidate genes. However, large sample sizes are required to achieve sufcient power. Multi-trait meta-analysis is one approach to deal with this prob- lem. Thus, we performed two multi-trait meta-analyses, one for three milk production traits (milk yield, protein yield and fat yield), and one for milk yield and mastitis resistance. Results: For highly correlated traits, the power to detect pleiotropy was increased by multi-trait meta-analysis com- pared with the subjective assessment of overlapping of single-trait QTL confdence intervals. Pleiotropic efects of lead single nucleotide polymorphisms (SNPs) that were detected from the multi-trait meta-analysis were confrmed by bivariate association analysis. The previously reported pleiotropic efects of variants within the DGAT1 and MGST1 genes on three milk production traits, and pleiotropic efects of variants in GHR on milk yield and fat yield were con- frmed.
    [Show full text]
  • Transcriptional Control of Tissue-Resident Memory T Cell Generation
    Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells.
    [Show full text]
  • Nuclear Factor I/B Is an Oncogene in Small Cell Lung Cancer
    Nuclear Factor I/B is an Oncogene in Small Cell Lung Cancer The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Dooley, A. L. et al. “Nuclear factor I/B is an oncogene in small cell lung cancer.” Genes & Development 25 (2011): 1470-1475. As Published http://dx.doi.org/10.1101/gad.2046711 Publisher Cold Spring Harbor Laboratory Press in association with The Genetics Society Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/66512 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike 3.0 Detailed Terms http://creativecommons.org/licenses/by-nc-sa/3.0/ Dooley 1 Nuclear Factor I/B is an Oncogene in Small Cell Lung Cancer Alison L. Dooley1, Monte M. Winslow1, Derek Y. Chiang2,3,4, Shantanu Banerji2,3, Nicolas Stransky2, Talya L. Dayton1, Eric L. Snyder1, Stephanie Senna1, Charles A. Whittaker1, Roderick T. Bronson5, Denise Crowley1, Jordi Barretina2,3, Levi Garraway2,3, Matthew Meyerson2,3, Tyler Jacks1,6 1David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA 2The Broad Institute, Cancer Program, Cambridge, Massachusetts, USA 3Dana-Farber Cancer Institute, Department of Medical Oncology and Center for Cancer Genome Discovery, Boston, Massachusetts, USA 4Current address: Lineberger Comprehensive Cancer Center, 450 West Drive, CB #7295, Chapel Hill, North Carolina, USA 5Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, North Grafton, Massachusetts, USA 6Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Key Words: Small Cell Lung Cancer, Mouse model, Nuclear Factor I/B Dooley 2 Abstract Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized.
    [Show full text]
  • Implication of M6a Mrna Methylation in Susceptibility to Inflammatory
    epigenomes Article Implication of m6A mRNA Methylation in Susceptibility to Inflammatory Bowel Disease Maialen Sebastian-delaCruz 1,2 , Ane Olazagoitia-Garmendia 1,2 , Itziar Gonzalez-Moro 2,3 , Izortze Santin 2,3,4 , Koldo Garcia-Etxebarria 5 and Ainara Castellanos-Rubio 1,2,4,6,* 1 Department of Genetics, Physical Anthropology and Animal Fisiology, University of the Basque Country, 48940 Leioa, Spain; [email protected] (M.S.-d.); [email protected] (A.O.-G.) 2 Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; [email protected] (I.G.-M.); [email protected] (I.S.) 3 Department of Biochemistry and Molecular Biology, University of the Basque Country, 48940 Leioa, Spain 4 CIBER (Centro de Investigación Biomédica en Red) de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain 5 Hepatic and Gastrointestinal Disease Area, IIS Biodonostia, 20014 Donostia, Spain; [email protected] 6 Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain * Correspondence: [email protected] Received: 29 June 2020; Accepted: 28 July 2020; Published: 3 August 2020 Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that develops due to the interaction between genetic and environmental factors. More than 160 loci have been associated with IBD, but the functional implication of many of the associated genes remains unclear. N6-Methyladenosine (m6A) is the most abundant internal modification in mRNA. m6A methylation regulates many aspects of mRNA metabolism, playing important roles in the development of several pathologies. Interestingly, SNPs located near or within m6A motifs have been proposed as possible contributors to disease pathogenesis.
    [Show full text]
  • Essential Genes and Their Role in Autism Spectrum Disorder
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Essential Genes And Their Role In Autism Spectrum Disorder Xiao Ji University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, and the Genetics Commons Recommended Citation Ji, Xiao, "Essential Genes And Their Role In Autism Spectrum Disorder" (2017). Publicly Accessible Penn Dissertations. 2369. https://repository.upenn.edu/edissertations/2369 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2369 For more information, please contact [email protected]. Essential Genes And Their Role In Autism Spectrum Disorder Abstract Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific oler in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality.
    [Show full text]