Phenotypic Annotation of the Mouse X Chromosome Brian J. Cox , Marion
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Mechanism-Anchored Profiling Derived from Epigenetic Networks Predicts Outcome in Acute Lymphoblastic Leukemia Xinan Yang, PhD1, Yong Huang, MD1, James L Chen, MD1, Jianming Xie, MSc2, Xiao Sun, PhD2, Yves A Lussier, MD1,3,4§ 1Center for Biomedical Informatics and Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637 USA 2State Key Laboratory of Bioelectronics, Southeast University, 210096 Nanjing, P.R.China 3The University of Chicago Cancer Research Center, and The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637 USA 4The Institute for Genomics and Systems Biology, and the Computational Institute, The University of Chicago, Chicago, IL 60637 USA §Corresponding author Email addresses: XY: [email protected] YH: [email protected] JC: [email protected] JX: [email protected] XS: [email protected] YL: [email protected] - 1 - Abstract Background Current outcome predictors based on “molecular profiling” rely on gene lists selected without consideration for their molecular mechanisms. This study was designed to demonstrate that we could learn about genes related to a specific mechanism and further use this knowledge to predict outcome in patients – a paradigm shift towards accurate “mechanism-anchored profiling”. We propose a novel algorithm, PGnet, which predicts a tripartite mechanism-anchored network associated to epigenetic regulation consisting of phenotypes, genes and mechanisms. Genes termed as GEMs in this network meet all of the following criteria: (i) they are co-expressed with genes known to be involved in the biological mechanism of interest, (ii) they are also differentially expressed between distinct phenotypes relevant to the study, and (iii) as a biomodule, genes correlate with both the mechanism and the phenotype. -
Dynamics of Gene Silencing During X Inactivation Using Allele-Specific RNA-Seq Hendrik Marks1*, Hindrik H
Marks et al. Genome Biology (2015) 16:149 DOI 10.1186/s13059-015-0698-x RESEARCH Open Access Dynamics of gene silencing during X inactivation using allele-specific RNA-seq Hendrik Marks1*, Hindrik H. D. Kerstens1, Tahsin Stefan Barakat3, Erik Splinter4, René A. M. Dirks1, Guido van Mierlo1, Onkar Joshi1, Shuang-Yin Wang1, Tomas Babak5, Cornelis A. Albers2, Tüzer Kalkan6, Austin Smith6, Alice Jouneau7, Wouter de Laat4, Joost Gribnau3 and Hendrik G. Stunnenberg1* Abstract Background: During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells, which contain a single X chromosome. Here, we use mouse female embryonic stem cells (ESCs) with non-random X chromosome inactivation (XCI) and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome by high-resolution allele-specific RNA-seq. Results: Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Allele-specific RNA-seq of neural progenitor cells generated from the female ESCs identifies three regions distal to the X-inactivation center that escape XCI. These regions, which stably escape during propagation and maintenance of XCI, coincide with topologically associating domains (TADs) as present in the female ESCs. -
The HECT Domain Ubiquitin Ligase HUWE1 Targets Unassembled Soluble Proteins for Degradation
OPEN Citation: Cell Discovery (2016) 2, 16040; doi:10.1038/celldisc.2016.40 ARTICLE www.nature.com/celldisc The HECT domain ubiquitin ligase HUWE1 targets unassembled soluble proteins for degradation Yue Xu1, D Eric Anderson2, Yihong Ye1 1Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; 2Advanced Mass Spectrometry Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA In eukaryotes, many proteins function in multi-subunit complexes that require proper assembly. To maintain complex stoichiometry, cells use the endoplasmic reticulum-associated degradation system to degrade unassembled membrane subunits, but how unassembled soluble proteins are eliminated is undefined. Here we show that degradation of unassembled soluble proteins (referred to as unassembled soluble protein degradation, USPD) requires the ubiquitin selective chaperone p97, its co-factor nuclear protein localization protein 4 (Npl4), and the proteasome. At the ubiquitin ligase level, the previously identified protein quality control ligase UBR1 (ubiquitin protein ligase E3 component n-recognin 1) and the related enzymes only process a subset of unassembled soluble proteins. We identify the homologous to the E6-AP carboxyl terminus (homologous to the E6-AP carboxyl terminus) domain-containing protein HUWE1 as a ubiquitin ligase for substrates bearing unshielded, hydrophobic segments. We used a stable isotope labeling with amino acids-based proteomic approach to identify endogenous HUWE1 substrates. Interestingly, many HUWE1 substrates form multi-protein com- plexes that function in the nucleus although HUWE1 itself is cytoplasmically localized. Inhibition of nuclear entry enhances HUWE1-mediated ubiquitination and degradation, suggesting that USPD occurs primarily in the cytoplasm. -
The Results of an X-Chromosome Exome Sequencing Study
Open Access Research BMJ Open: first published as 10.1136/bmjopen-2015-009537 on 29 April 2016. Downloaded from HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study Michael J Friez,1 Susan Sklower Brooks,2 Roger E Stevenson,1 Michael Field,3 Monica J Basehore,1 Lesley C Adès,4 Courtney Sebold,5 Stephen McGee,1 Samantha Saxon,1 Cindy Skinner,1 Maria E Craig,4 Lucy Murray,3 Richard J Simensen,1 Ying Yzu Yap,6 Marie A Shaw,6 Alison Gardner,6 Mark Corbett,6 Raman Kumar,6 Matthias Bosshard,7 Barbara van Loon,7 Patrick S Tarpey,8 Fatima Abidi,1 Jozef Gecz,6 Charles E Schwartz1 To cite: Friez MJ, Brooks SS, ABSTRACT et al Strengths and limitations of this study Stevenson RE, . HUWE1 Background: X linked intellectual disability (XLID) mutations in Juberg-Marsidi syndromes account for a substantial number of males ▪ and Brooks syndromes: the Using the power of next generation sequencing, with ID. Much progress has been made in identifying results of an X-chromosome we have linked Juberg-Marsidi syndrome ( JMS) exome sequencing study. the genetic cause in many of the syndromes described and Brooks syndrome as allelic conditions. – BMJ Open 2016;6:e009537. 20 40 years ago. Next generation sequencing (NGS) ▪ This study provides better organisation to the doi:10.1136/bmjopen-2015- has contributed to the rapid discovery of XLID genes field of X linked disorders by providing evidence 009537 and identifying novel mutations in known XLID genes that JMS is not caused by mutation in the ATRX for many of these syndromes. -
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Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes. -
Instability of the Pseudoautosomal Boundary in House Mice
Genetics: Early Online, published on April 26, 2019 as 10.1534/genetics.119.302232 Article/Investigation Instability of the pseudoautosomal boundary in house mice Andrew P Morgan∗, Timothy A Bell∗, James J Crowley∗; y; z, and Fernando Pardo-Manuel de Villena∗ ∗Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC yDepartment of Psychiatry, University of North Carolina, Chapel Hill, NC zDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden April 26, 2019 Corresponding authors: Andrew P Morgan ([email protected]) Fernando Pardo-Manuel de Villena ([email protected]) 5049C Genetic Medicine Building Department of Genetics University of North Carolina Chapel Hill NC 27599-7264 Keywords: meiosis, recombination, pseudoautosomal region, sex chromosome evolution 1 Copyright 2019. Abstract Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow inter- val of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here we estimate the genetic map in a previously-documented ex- pansion of the PAR in the Mus musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the Mus musculus musculus subspecies and show that it involves a complex rearrangement but still recombines in heterozygous males. -
Centre for Arab Genomic Studies a Division of Sheikh Hamdan Award for Medical Sciences
Centre for Arab Genomic Studies A Division of Sheikh Hamdan Award for Medical Sciences The Catalogue for Transmission Genetics in Arabs CTGA Database tRNA Methyltransferase 1, S. Cerevisiae, Homolog of Alternative Names planus. These findings are further bolstered by the TRMT1 fact that mutations in two other RNA- N2,N2-Dimethylguanosine-26 tRNA methyltransferase genes, NSUN2 and FTSJ1, have Methyltransferase been associated with intellectual disability. tRNA(m(2,2)G26)Dimethyltransferase Record Category Molecular Genetics Gene locus The TRMT1 gene is located on the short arm of chromosome 19 and spans a length of 12.6 kb of WHO-ICD DNA. Its coding sequence is spread across 18 N/A to gene loci exons and it encodes a 72.2 kDa protein product comprised of 659 amino acids. An additional 69.3 Incidence per 100,000 Live Births kDa isoform of the TRMT1 protein exists due to an N/A to gene loci alternatively spliced transcript variant. The gene is widely expressed in the human body, particularly in OMIM Number the nervous system, intestine, spleen, kidney and 611669 lung. Mode of Inheritance Epidemiology in the Arab World N/A to gene loci Saudi Arabia Monies et al. (2017) studied the findings of 1000 Gene Map Locus diagnostic panels and exomes carried out at a next 19p13.13 generation sequencing lab in Saudi Arabia. One patient, a 13-year-old male, presented with speech Description delay, intellectual disability, learning disability, The TRMT1 gene encodes a methyltransferase hypotonia and seizures. Using whole exome enzyme that acts on tRNA. This enzyme, which sequencing, a homozygous mutation consists of a zinc finger motif and an (c.1245_1246del, p.L415fs) was identified in exon arginine/proline rich region at its C-terminus, is 10 of the patient’s TRMT1 gene. -
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. -
Identification of Protein Complexes Associated with Myocardial Infarction Using a Bioinformatics Approach
MOLECULAR MEDICINE REPORTS 18: 3569-3576, 2018 Identification of protein complexes associated with myocardial infarction using a bioinformatics approach NIANHUI JIAO1, YONGJIE QI1, CHANGLI LV2, HONGJUN LI3 and FENGYONG YANG1 1Intensive Care Unit; 2Emergency Department, Laiwu People's Hospital, Laiwu, Shandong 271199; 3Emergency Department, The Central Hospital of Tai'an, Tai'an, Shandong 271000, P.R. China Received November 3, 2016; Accepted January 3, 2018 DOI: 10.3892/mmr.2018.9414 Abstract. Myocardial infarction (MI) is a leading cause of clinical outcomes regarding high-risk MI. For example, muta- mortality and disability worldwide. Determination of the tions in the myocardial infarction-associated transcript have molecular mechanisms underlying the disease is crucial for been reported to cause susceptibility to MI (5). In addition, it identifying possible therapeutic targets and designing effective was demonstrated that mutations in the oxidized low-density treatments. On the basis that MI may be caused by dysfunc- lipoprotein receptor 1 gene may significantly increase the tional protein complexes rather than single genes, the present risk of MI (6). Although some MI-related genes have been study aimed to use a bioinformatics approach to identifying detected, many were identified independently and functional complexes that may serve important roles in the develop- associations among the genes have rarely been explored. ment of MI. By investigating the proteins involved in these Therefore, it is necessary to investigate MI from a systematic identified complexes, numerous proteins have been reported perspective, as the complex disease was reported to occur due that are related to MI, whereas other proteins interacted to the dysregulation of functional gene sets (7). -
WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US). -
SLIC-CAGE: High-Resolution Transcription Start Site Mapping Using Nanogram-Levels of Total RNA
bioRxiv preprint doi: https://doi.org/10.1101/368795; this version posted July 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 4.0 International license. SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA Nevena Cvetesic1, 2*, Harry G. Leitch1,2, Malgorzata Borkowska1,2, Ferenc Müller3, Piero Carninci4,5, Petra Hajkova1,2 and Boris Lenhard1,2,6* 1Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK 2MRC London Institute of Medical Sciences, London W12 0NN, UK 3Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston B15 2TT, UK 4RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama City, Kanagawa 230-0045, Japan 5RIKEN Omics Science Center, Yokohama City, Kanagawa 230-0045, Japan 6Sars International Centre for Marine Molecular Biology, University of Bergen, N-5008 Bergen, Norway *Correspondence to: Nevena Cvetesic Institute of Clinical Sciences, Faculty of Medicine, Imperial College London and MRC London Institute of Medical Sciences, London, W12 0NN, UK e-mail: [email protected] Boris Lenhard Institute of Clinical Sciences, Faculty of Medicine, Imperial College London and MRC London Institute of Medical Sciences, London, W12 0NN, UK e-mail: [email protected] Running title: TSS discovery using Super-Low Input Carrier-CAGE Keywords: cap analysis of gene expression; low input material; degradable nucleic acid carrier; promoters; gene expression profiling 1 bioRxiv preprint doi: https://doi.org/10.1101/368795; this version posted July 19, 2018. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase