SNP) at Codon 72 of P53 in the Innate Immune Response Against Virus Infection
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Core Transcriptional Regulatory Circuitries in Cancer
Oncogene (2020) 39:6633–6646 https://doi.org/10.1038/s41388-020-01459-w REVIEW ARTICLE Core transcriptional regulatory circuitries in cancer 1 1,2,3 1 2 1,4,5 Ye Chen ● Liang Xu ● Ruby Yu-Tong Lin ● Markus Müschen ● H. Phillip Koeffler Received: 14 June 2020 / Revised: 30 August 2020 / Accepted: 4 September 2020 / Published online: 17 September 2020 © The Author(s) 2020. This article is published with open access Abstract Transcription factors (TFs) coordinate the on-and-off states of gene expression typically in a combinatorial fashion. Studies from embryonic stem cells and other cell types have revealed that a clique of self-regulated core TFs control cell identity and cell state. These core TFs form interconnected feed-forward transcriptional loops to establish and reinforce the cell-type- specific gene-expression program; the ensemble of core TFs and their regulatory loops constitutes core transcriptional regulatory circuitry (CRC). Here, we summarize recent progress in computational reconstitution and biologic exploration of CRCs across various human malignancies, and consolidate the strategy and methodology for CRC discovery. We also discuss the genetic basis and therapeutic vulnerability of CRC, and highlight new frontiers and future efforts for the study of CRC in cancer. Knowledge of CRC in cancer is fundamental to understanding cancer-specific transcriptional addiction, and should provide important insight to both pathobiology and therapeutics. 1234567890();,: 1234567890();,: Introduction genes. Till now, one critical goal in biology remains to understand the composition and hierarchy of transcriptional Transcriptional regulation is one of the fundamental mole- regulatory network in each specified cell type/lineage. -
The Role of Type I Interferon in the Immunobiology of Chikungunya Virus
The role of type I interferon in the immunobiology of chikungunya virus Jane Amelia Clare Wilson B. App. Sc. (Human Biology), B. App. Sc. (Hons) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2015 School of Medicine & QIMR Berghofer Medical Research Institute I Abstract Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause explosive outbreaks of a febrile, arthritic/arthralgic disease usually lasting weeks to months, and in rare cases, more than a year. In 2004, the largest ever CHIKV outbreak began in Kenya, spreading to islands of the Indian Ocean, India, South East Asia and major outbreaks have recently occurred in the South Pacific Islands and the Caribbean. The host type I interferon (IFN) response is crucial for effective control of CHIKV infection. Herein, the dynamics, source and responses generated by the type I IFNs following CHIKV infection were investigated. Interferon regulatory factors 3 (IRF3) and IRF7 are key transcription factors for the type I IFN response. While CHIKV infection of wild-type mice is non-lethal, infection of mice deficient in both IRF3 and IRF7 (IRF3/7-/-) resulted in mortality, illustrating that these factors are essential for protection. Using knockout mice for the adaptor molecules upstream of IRF3 and 7, IPS1 was found to be the most important for type I IFN production, with TRIF and MyD88 also contributing to the response. Mortality in IRF3/7-/- mice was also associated with type I IFN suppression of pathological levels of IFNγ and haemorrhagic shock. Heterozygous reporter mice, in which eGFP was expressed under the control of either the IFNβ or the IFNα6 promoter on one chromosome, were employed to try and identify the cellular source of type I IFN production following CHIVK infection. -
Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug
cancers Article Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia David G.J. Cucchi 1 , Costa Bachas 1 , Marry M. van den Heuvel-Eibrink 2,3, Susan T.C.J.M. Arentsen-Peters 3, Zinia J. Kwidama 1, Gerrit J. Schuurhuis 1, Yehuda G. Assaraf 4, Valérie de Haas 3 , Gertjan J.L. Kaspers 3,5 and Jacqueline Cloos 1,* 1 Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (D.G.J.C.); [email protected] (C.B.); [email protected] (Z.J.K.); [email protected] (G.J.S.) 2 Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands; [email protected] 3 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; [email protected] (S.T.C.J.M.A.-P.); [email protected] (V.d.H.); [email protected] (G.J.L.K.) 4 The Fred Wyszkowski Cancer Research, Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200003 Haifa, Israel; [email protected] 5 Emma’s Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands * Correspondence: [email protected] Received: 21 April 2020; Accepted: 12 May 2020; Published: 15 May 2020 Abstract: Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. -
UNIVERSITY of CALIFORNIA, IRVINE Combinatorial Regulation By
UNIVERSITY OF CALIFORNIA, IRVINE Combinatorial regulation by maternal transcription factors during activation of the endoderm gene regulatory network DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Kitt D. Paraiso Dissertation Committee: Professor Ken W.Y. Cho, Chair Associate Professor Olivier Cinquin Professor Thomas Schilling 2018 Chapter 4 © 2017 Elsevier Ltd. © 2018 Kitt D. Paraiso DEDICATION To the incredibly intelligent and talented people, who in one way or another, helped complete this thesis. ii TABLE OF CONTENTS Page LIST OF FIGURES vii LIST OF TABLES ix LIST OF ABBREVIATIONS X ACKNOWLEDGEMENTS xi CURRICULUM VITAE xii ABSTRACT OF THE DISSERTATION xiv CHAPTER 1: Maternal transcription factors during early endoderm formation in 1 Xenopus Transcription factors co-regulate in a cell type-specific manner 2 Otx1 is expressed in a variety of cell lineages 4 Maternal otx1 in the endodermal conteXt 5 Establishment of enhancers by maternal transcription factors 9 Uncovering the endodermal gene regulatory network 12 Zygotic genome activation and temporal control of gene eXpression 14 The role of maternal transcription factors in early development 18 References 19 CHAPTER 2: Assembly of maternal transcription factors initiates the emergence 26 of tissue-specific zygotic cis-regulatory regions Introduction 28 Identification of maternal vegetally-localized transcription factors 31 Vegt and OtX1 combinatorially regulate the endodermal 33 transcriptome iii -
Integration of 198 Chip-Seq Datasets Reveals Human Cis-Regulatory Regions
Integration of 198 ChIP-seq datasets reveals human cis-regulatory regions Hamid Bolouri & Larry Ruzzo Thanks to Stephen Tapscott, Steven Henikoff & Zizhen Yao Slides will be available from: http://labs.fhcrc.org/bolouri/ Email [email protected] for manuscript (Bolouri & Ruzzo, submitted) Kleinjan & van Heyningen, Am. J. Hum. Genet., 2005, (76)8–32 Epstein, Briefings in Func. Genom. & Protemoics, 2009, 8(4)310-16 Regulation of SPi1 (Sfpi1, PU.1 protein) expression – part 1 miR155*, miR569# ~750nt promoter ~250nt promoter The antisense RNA • causes translational stalling • has its own promoter • requires distal SPI1 enhancer • is transcribed with/without SPI1. # Hikami et al, Arthritis & Rheumatism, 2011, 63(3):755–763 * Vigorito et al, 2007, Immunity 27, 847–859 Ebralidze et al, Genes & Development, 2008, 22: 2085-2092. Regulation of SPi1 expression – part 2 (mouse coordinates) Bidirectional ncRNA transcription proportional to PU.1 expression PU.1/ELF1/FLI1/GLI1 GATA1 GATA1 Sox4/TCF/LEF PU.1 RUNX1 SP1 RUNX1 RUNX1 SP1 ELF1 NF-kB SATB1 IKAROS PU.1 cJun/CEBP OCT1 cJun/CEBP 500b 500b 500b 500b 500b 750b 500b -18Kb -14Kb -12Kb -10Kb -9Kb Chou et al, Blood, 2009, 114: 983-994 Hoogenkamp et al, Molecular & Cellular Biology, 2007, 27(21):7425-7438 Zarnegar & Rothenberg, 2010, Mol. & cell Biol. 4922-4939 An NF-kB binding-site variant in the SPI1 URE reduces PU.1 expression & is GGGCCTCCCC correlated with AML GGGTCTTCCC Bonadies et al, Oncogene, 2009, 29(7):1062-72. SATB1 binding site A distal single nucleotide polymorphism alters long- range regulation of the PU.1 gene in acute myeloid leukemia Steidl et al, J Clin Invest. -
Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage Fd Targeted to DEC-205
Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 585078, 11 pages http://dx.doi.org/10.1155/2015/585078 Research Article Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage fd Targeted to DEC-205 Luciana D’Apice,1 Valerio Costa,2 Rossella Sartorius,1 Maria Trovato,1 Marianna Aprile,2 and Piergiuseppe De Berardinis1 1 Institute of Protein Biochemistry (IBP), National Council of Research, 80131 Naples, Italy 2Institute of Genetics and Biophysics “A. Buzzati-Traverso” (IGB), National Council of Research, 80131 Naples, Italy Correspondence should be addressed to Luciana D’Apice; [email protected] Received 26 March 2015; Accepted 27 May 2015 Academic Editor: L. Leite Copyright © 2015 Luciana D’Apice et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The filamentous bacteriophage fd, codisplaying antigenic determinants and a single chain antibody fragment directed against the dendritic cell receptor DEC-205, is a promising vaccine candidate for its safety and its ability to elicit innate and adaptive immune response in absence of adjuvants. By using a system vaccinology approach based on RNA-Sequencing (RNA-Seq) analysis, we describe a relevant gene modulation in dendritic cells pulsed with anti-DEC-205 bacteriophages fd. RNA-Seq data analysis indicates that the bacteriophage fd virions are sensed as a pathogen by dendritic cells; they activate the danger receptors that trigger an innate immune response and thus confer a strong adjuvanticity that is needed to obtain a long-lasting adaptive immune response. -
Type I Interferon Remodels Lysosome Function and Modifies Intestinal Epithelial Defense
Type I interferon remodels lysosome function and modifies intestinal epithelial defense Hailong Zhanga,b,c, Abdelrahim Zoueda,b,c, Xu Liua,b,c, Brandon Sitb,c, and Matthew K. Waldora,b,c,1 aHoward Hughes Medical Insitute, Boston, MA 02115; bDivision of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA 02115; and cDepartment of Microbiology, Harvard Medical School, Boston, MA 02115 Edited by Jorge E. Galán, Yale University, New Haven, CT, and approved October 14, 2020 (received for review May 29, 2020) Organelle remodeling is critical for cellular homeostasis, but host the full spectrum of IFN-I-mediated changes in cellular function factors that control organelle function during microbial infection is incomplete. Although IFN-Is are known to play critical roles in remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 antiviral responses, their functions in bacterial infection are less screen in intestinal epithelial cells with the prototypical intracellu- clear, and IFN-I signaling has been reported to be either pro- lar bacterial pathogen Salmonella led us to discover that type I IFN tective or detrimental to the host depending on the specific (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I bacterial pathogen (19). signaling modified the localization, acidification, protease activity, Here, we carried out a genome-scale CRISPR/Cas9 screen to and proteomic profile of lysosomes. Proteomic and genetic analyses identify the host factors that contribute to Stm’s cytotoxicity to revealed that multiple IFN-I–stimulated genes including IFITM3, SLC15A3, IECs. This screen revealed IFN-I signaling as a key susceptibility and CNP contribute to lysosome acidification. -
Virtual Chip-Seq: Predicting Transcription Factor Binding
bioRxiv preprint doi: https://doi.org/10.1101/168419; this version posted March 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Virtual ChIP-seq: predicting transcription factor binding 2 by learning from the transcriptome 1,2,3 1,2,3,4,5 3 Mehran Karimzadeh and Michael M. Hoffman 1 4 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada 2 5 Princess Margaret Cancer Centre, Toronto, ON, Canada 3 6 Vector Institute, Toronto, ON, Canada 4 7 Department of Computer Science, University of Toronto, Toronto, ON, Canada 5 8 Lead contact: michael.hoff[email protected] 9 March 8, 2019 10 Abstract 11 Motivation: 12 Identifying transcription factor binding sites is the first step in pinpointing non-coding mutations 13 that disrupt the regulatory function of transcription factors and promote disease. ChIP-seq is 14 the most common method for identifying binding sites, but performing it on patient samples is 15 hampered by the amount of available biological material and the cost of the experiment. Existing 16 methods for computational prediction of regulatory elements primarily predict binding in genomic 17 regions with sequence similarity to known transcription factor sequence preferences. This has limited 18 efficacy since most binding sites do not resemble known transcription factor sequence motifs, and 19 many transcription factors are not even sequence-specific. 20 Results: 21 We developed Virtual ChIP-seq, which predicts binding of individual transcription factors in new 22 cell types using an artificial neural network that integrates ChIP-seq results from other cell types 23 and chromatin accessibility data in the new cell type. -
Microglial Responses to Peripheral Type 1 Interferon Ernest Aw1,2, Yingying Zhang1 and Michael Carroll1*
Aw et al. Journal of Neuroinflammation (2020) 17:340 https://doi.org/10.1186/s12974-020-02003-z RESEARCH Open Access Microglial responses to peripheral type 1 interferon Ernest Aw1,2, Yingying Zhang1 and Michael Carroll1* Abstract Background: Interferon α (IFNα) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFNα signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFNα signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFNα modulates these functions are not well defined. Methods: Using a model of peripheral IFNα administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFNα and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFNα on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. Results: We found that IFNα exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFNα-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region- specific differences. -
Combined Genetic and Transcriptome Analysis of Patients With
Systemic lupus erythematosus Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214379 on 5 June 2019. Downloaded from TRANSLATIONAL SCIENCE Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity Nikolaos I Panousis, 1,2,3 George K Bertsias, 4,5 Halit Ongen,1,2,3 Irini Gergianaki,4,5 Maria G Tektonidou, 6,7 Maria Trachana,8 Luciana Romano-Palumbo,1 Deborah Bielser,1 Cedric Howald,1,2,3 Cristina Pamfil,9 Antonis Fanouriakis, 10 Despoina Kosmara,4,5 Argyro Repa,4 Prodromos Sidiropoulos,4,5 Emmanouil T Dermitzakis,1,2,3,11 Dimitrios T Boumpas5,7,10,11,12 Handling editor Josef S ABSTRact Key messages Smolen Objectives Systemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the ► Additional material is What is already known about this subject? published online only. To view molecular basis for its heterogeneity elusive. We explored ► Previous DNA microarray gene expression please visit the journal online the genomic basis for disease susceptibility and severity. studies have identified gene signatures (http:// dx. doi. org/ 10. 1136/ Methods mRNA sequencing and genotyping in blood involved in systemic lupus erythematosus (SLE) annrheumdis- 2018- 214379). from 142 patients with SLE and 58 healthy volunteers. such as those linked to granulocytes, pattern Abundances of cell types were assessed by CIBERSORT For numbered affiliations see recognition receptors, type I interferon and and cell-specific effects by interaction terms in linear end of article. plasmablasts. models. Differentially expressed genes (DEGs) were used Correspondence to to train classifiers (linear discriminant analysis) of SLE What does this study add? Professor Emmanouil T versus healthy individuals in 80% of the dataset and A more comprehensive profiling of the ‘genomic Dermitzakis, Department of were validated in the remaining 20% running 1000 ► Genetic Medicine and architecture’ of SLE by combining genetic and iterations. -
Role of Estrogen Receptor in Breast Cancer Cell Gene Expression
4046 MOLECULAR MEDICINE REPORTS 13: 4046-4050, 2016 Role of estrogen receptor in breast cancer cell gene expression YABING ZHENG1, XIYING SHAO1, YUAN HUANG1, LEI SHI1, BO CHEN2, XIAOJIA WANG1, HONGJIAN YANG3, ZHANHONG CHEN1 and XIPING ZHANG3 Departments of 1Medical Oncology (Breast), 2Pathology and 3Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China Received April 28, 2015; Accepted February 23, 2016 DOI: 10.3892/mmr.2016.5018 Abstract. The aim of the present study was to establish the Europe in 2012, and the number of breast cancer-associated underlying regulatory mechanism of estrogen receptor (ER) mortalities is 131,000 (6). Furthermore, breast cancer is in breast cancer cell gene expression. A gene expression the most common cause of cancer-associated mortality in profile accession( no. GSE11324) was downloaded from the females. Therefore, it is essential to understand its molecular Gene Expression Omnibus (GEO) database. Differentially mechanism and develop more effective therapeutic methods expressed genes (DEGs) from an estrogen treatment group and for breast cancer treatment. a control group were identified. Chromatin immunoprecipita- The estrogen receptor (ER) is critical in determining the tion with high-throughput sequencing data (series GSE25710) phenotype of human breast cancers and is one of the most was obtained from the GEO for the ER binding sites, and important therapeutic targets (7). Furthermore, certain studies binding and expression target analysis was performed. A total have suggested that activation of ER is responsible for various of 3,122 DEGs were obtained and ER was demonstrated to biological processes, including cell growth and differentia- exhibit inhibition and activation roles during the regulation tion, and programmed cell death (8,9). -
Integrated Computational Approach to the Analysis of RNA-Seq Data Reveals New Transcriptional Regulators of Psoriasis
OPEN Experimental & Molecular Medicine (2016) 48, e268; doi:10.1038/emm.2016.97 & 2016 KSBMB. All rights reserved 2092-6413/16 www.nature.com/emm ORIGINAL ARTICLE Integrated computational approach to the analysis of RNA-seq data reveals new transcriptional regulators of psoriasis Alena Zolotarenko1, Evgeny Chekalin1, Alexandre Mesentsev1, Ludmila Kiseleva2, Elena Gribanova2, Rohini Mehta3, Ancha Baranova3,4,5,6, Tatiana V Tatarinova6,7,8, Eleonora S Piruzian1 and Sergey Bruskin1,5 Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFκB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyper- proliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the (CD4+FOXA1+CD47+CD69+PD-L1(hi) FOXP3 − ) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions.