Identifying and Exploiting Gene-Pathway Interactions from RNA-Seq Data for Binary Phenotype Fang Shao1, Yaqi Wang2, Yang Zhao1 and Sheng Yang1*
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SAN TA C RUZ BI OTEC HNOL OG Y, INC . TRIM (M-187): sc-366296 BACKGROUND APPLICATIONS TRIM (T-cell receptor interacting molecule) is a novel transmembrane adap tor TRIM (M-187) is recommended for detection of TRIM of mouse, rat and, to protein which associates and comodulates with the TCR-CD3 ζ complex in a lesser extent, human origin by Western Blotting (starting dilution 1:200, human T lymphocytes and T cell lines. TRIM is a type III transmembrane dilution range 1:100-1:1000), immunoprecipitation [1-2 µg per 100-500 µg pro tein that contains an 8-amino acid extracellular domain and an intracellu - of total protein (1 ml of cell lysate)], immunofluorescence (starting dilution lar domain that contains 4 potential phosphorylation sites and 8 tyrosine 1:50, dilution range 1:50-1:500) and solid phase ELISA (starting dilution 1:30, residues, at least 3 of which may be involved in SH2-mediated interactions dilution range 1:30-1:3000). with other signaling proteins. The human TRIM gene maps to chromosome Suitable for use as control antibody for TRIM siRNA (h): sc-106637, TRIM 3q13.13, which is a susceptibility locus for rheumatoid arthritis and is in siRNA (m): sc-154641, TRIM shRNA Plasmid (h): sc-106637-SH, TRIM shRNA proximity to the CD28, CD86, and CD80 genes, all of which encode T-cell Plasmid (m): sc-154641-SH, TRIM shRNA (h) Lentiviral Particles: sc-106637-V costimulatory molecules. TRIM is expressed in T-cells and natural killer cells, and TRIM shRNA (m) Lentiviral Particles: sc-154641-V. -
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. -
Histone H3.3 Maintains Genome Integrity During Mammalian Development
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Histone H3.3 maintains genome integrity during mammalian development Chuan-Wei Jang, Yoichiro Shibata, Joshua Starmer, Della Yee, and Terry Magnuson Department of Genetics, Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans and has been implicated in many important biological processes, including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components or in H3.3 encoding genes have been associated with human congenital diseases and cancers, respectively. However, the role of H3.3 in mammalian development remains un- clear. To address this question, we generated H3.3-null mouse models through classical genetic approaches. We found that H3.3 plays an essential role in mouse development. Complete depletion of H3.3 leads to developmental retardation and early embryonic lethality. At the cellular level, H3.3 loss triggers cell cycle suppression and cell death. Surprisingly, H3.3 depletion does not dramatically disrupt gene regulation in the developing embryo. Instead, H3.3 depletion causes dysfunction of heterochromatin structures at telomeres, centromeres, and pericentromeric regions of chromosomes, leading to mitotic defects. The resulting karyotypical abnormalities and DNA damage lead to p53 pathway activation. In summary, our results reveal that an important function of H3.3 is to support chro- mosomal heterochromatic structures, thus maintaining genome integrity during mammalian development. [Keywords: histone H3.3; genome integrity; transcriptional regulation; cell proliferation; apoptosis; mouse embryonic development] Supplemental material is available for this article. -
CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells With
+ CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells. -
Análise Integrativa De Perfis Transcricionais De Pacientes Com
UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. -
Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology. -
UC Davis UC Davis Previously Published Works
UC Davis UC Davis Previously Published Works Title Endogenous mammalian histone H3.3 exhibits chromatin-related functions during development Permalink https://escholarship.org/uc/item/4c96g6pw Journal Epigenetics & Chromatin, 6(1) ISSN 1756-8935 Authors Bush, Kelly M Yuen, Benjamin TK Barrilleaux, Bonnie L et al. Publication Date 2013-04-09 DOI http://dx.doi.org/10.1186/1756-8935-6-7 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Bush et al. Epigenetics & Chromatin 2013, 6:7 http://www.epigeneticsandchromatin.com/content/6/1/7 RESEARCH Open Access Endogenous mammalian histone H3.3 exhibits chromatin-related functions during development Kelly M Bush1,2,3, Benjamin TK Yuen1,2,3, Bonnie L Barrilleaux1,2,3, John W Riggs1,2,3, Henriette O’Geen2, Rebecca F Cotterman1,2,3 and Paul S Knoepfler1,2,3* Abstract Background: The histone variant H3.3 plays key roles in regulating chromatin states and transcription. However, the role of endogenous H3.3 in mammalian cells and during development has been less thoroughly investigated. To address this gap, we report the production and phenotypic analysis of mice and cells with targeted disruption of the H3.3-encoding gene, H3f3b. Results: H3f3b knockout (KO) mice exhibit a semilethal phenotype traceable at least in part to defective cell division and chromosome segregation. H3f3b KO cells have widespread ectopic CENP-A protein localization suggesting one possible mechanism for defective chromosome segregation. KO cells have abnormal karyotypes and cell cycle profiles as well. The transcriptome and euchromatin-related epigenome were moderately affected by loss of H3f3b in mouse embryonic fibroblasts (MEFs) with ontology most notably pointing to changes in chromatin regulatory and histone coding genes. -
A Mutation in Histone H2B Represents a New Class of Oncogenic Driver
Author Manuscript Published OnlineFirst on July 23, 2019; DOI: 10.1158/2159-8290.CD-19-0393 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Mutation in Histone H2B Represents A New Class Of Oncogenic Driver Richard L. Bennett1, Aditya Bele1, Eliza C. Small2, Christine M. Will2, Behnam Nabet3, Jon A. Oyer2, Xiaoxiao Huang1,9, Rajarshi P. Ghosh4, Adrian T. Grzybowski5, Tao Yu6, Qiao Zhang7, Alberto Riva8, Tanmay P. Lele7, George C. Schatz9, Neil L. Kelleher9 Alexander J. Ruthenburg5, Jan Liphardt4 and Jonathan D. Licht1 * 1 Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL 2 Division of Hematology/Oncology, Northwestern University 3 Department of Cancer Biology, Dana Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School 4 Department of Bioengineering, Stanford University 5 Department of Molecular Genetics and Cell Biology, The University of Chicago 6 Department of Chemistry, Tennessee Technological University 7 Department of Chemical Engineering, University of Florida 8 Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida 9 Department of Chemistry, Northwestern University, Evanston IL 60208 Running title: Histone mutations in cancer *Corresponding Author: Jonathan D. Licht, MD The University of Florida Health Cancer Center Cancer and Genetics Research Complex, Suite 145 2033 Mowry Road Gainesville, FL 32610 352-273-8143 [email protected] Disclosures: The authors have no conflicts of interest to declare Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 23, 2019; DOI: 10.1158/2159-8290.CD-19-0393 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
Non-Neutral Evolution of H3.3-Encoding Genes Occurs Without Alterations in Protein Sequence
bioRxiv preprint doi: https://doi.org/10.1101/422311; this version posted September 25, 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 Non-neutral evolution of H3.3-encoding genes occurs without alterations in protein 2 sequence 3 4 Brejnev Muhire1, Matthew Booker1,2 and Michael Tolstorukov1,2,* 5 1Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical 6 School, Boston, MA 02114 7 2Dana-Farber Cancer Institute, Boston, MA 02215 8 9 *correspondence: [email protected] 10 11 Abstract 12 Histone H3.3 is a developmentally essential variant encoded by two independent genes in 13 human (H3F3A and H3F3B). While this two-gene arrangement is evolutionarily conserved, its 14 origins and function remain unknown. Phylogenetics, synteny and gene structure analyses of 15 the H3.3 genes from 32 metazoan genomes indicate independent evolutionary paths for H3F3A 16 and H3F3B. While H3F3B bears similarities with H3.3 genes in distant organisms and with 17 canonical H3 genes, H3F3A is sarcopterygian-specific and evolves under strong purifying 18 selection. Additionally, H3F3B codon-usage preferences resemble those of broadly expressed 19 genes and ‘cell differentiation-induced’ genes, while codon-usage of H3F3A resembles that of 20 ‘cell proliferation-induced’ genes. We infer that H3F3B is more similar to the ancestral H3.3 21 gene and likely evolutionarily adapted for broad expression pattern in diverse cellular programs, 22 while H3F3A adapted for a subset of gene expression programs. -
Sequence Specificity Analysis of the SETD2 Protein Lysine Methyltransferase and Discovery of a SETD2 Super-Substrate
ARTICLE https://doi.org/10.1038/s42003-020-01223-6 OPEN Sequence specificity analysis of the SETD2 protein lysine methyltransferase and discovery of a SETD2 super-substrate Maren Kirstin Schuhmacher1,4, Serap Beldar2,4, Mina S. Khella1,3,4, Alexander Bröhm1, Jan Ludwig1, ✉ ✉ 1234567890():,; Wolfram Tempel2, Sara Weirich1, Jinrong Min2 & Albert Jeltsch 1 SETD2 catalyzes methylation at lysine 36 of histone H3 and it has many disease connections. We investigated the substrate sequence specificity of SETD2 and identified nine additional peptide and one protein (FBN1) substrates. Our data showed that SETD2 strongly prefers amino acids different from those in the H3K36 sequence at several positions of its specificity profile. Based on this, we designed an optimized super-substrate containing four amino acid exchanges and show by quantitative methylation assays with SETD2 that the super-substrate peptide is methylated about 290-fold more efficiently than the H3K36 peptide. Protein methylation studies confirmed very strong SETD2 methylation of the super-substrate in vitro and in cells. We solved the structure of SETD2 with bound super-substrate peptide con- taining a target lysine to methionine mutation, which revealed better interactions involving three of the substituted residues. Our data illustrate that substrate sequence design can strongly increase the activity of protein lysine methyltransferases. 1 Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany. 2 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada. 3 Biochemistry Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, Cairo 11566, Egypt. 4These authors contributed equally: Maren Kirstin Schuhmacher, Serap Beldar, Mina S. -
A Genome Wide Screen in C. Elegans Identifies Cell Non-Autonomous Regulators of Oncogenic Ras Mediated Over-Proliferation DISSER
A genome wide screen in C. elegans identifies cell non-autonomous regulators of oncogenic Ras mediated over-proliferation DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Komal Rambani Graduate Program in Biomedical Sciences The Ohio State University 2016 Dissertation Committee: Gustavo Leone, PhD “Advisor" Helen Chamberlin, PhD Gregory Lesinski, PhD Joanna Groden, PhD Jeffrey Parvin, PhD Thomas Ludwig, PhD Copyright by Komal Rambani 2016 ABSTRACT Coordinated proliferative signals from the mesenchymal cells play a crucial role in the regulation of proliferation of epithelial cells during normal development, wound healing and several other normal physiological conditions. However, when epithelial cells acquire a set of malignant mutations, they respond differently to these extrinsic proliferative signals elicited by the surrounding mesenchymal cells. This scenario leads to a pathological signaling microenvironment that enhances abnormal proliferation of mutant epithelial cells and hence tumor growth. Despite mounting evidence that mesenchymal (stromal) cells influence the growth of tumors and cancer progression, it is unclear which specific genes in the mesenchymal cells regulate the molecular signals that promote the over-proliferation of the adjacent mutant epithelial cells. We hypothesized that there are certain genes in the mesenchymal (stromal) cells that regulate proliferation of the adjacent mutant cells. The complexity of various stromal cell types and their interactions in vivo in cancer mouse models and human tumor samples limits our ability to identify mesenchymal genes important in this process. Thus, we took a cross-species approach to use C. elegans vulval development as a model to understand the impact of mesenchymal (mesodermal) cells on the proliferation of epithelial (epidermal) cells. -
Germline Mutations in Histone 3 Family 3A and 3B Cause a Previously Unidentified Neurodegenerative Disorder in 46 Patients
Washington University School of Medicine Digital Commons@Becker Open Access Publications 2020 Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients Laura Bryant Marcia C Willing Linda Manwaring et al Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs SCIENCE ADVANCES | RESEARCH ARTICLE GENETICS Copyright © 2020 The Authors, some rights reserved; Histone H3.3 beyond cancer: Germline mutations in exclusive licensee American Association Histone 3 Family 3A and 3B cause a previously for the Advancement of Science. No claim to unidentified neurodegenerative disorder in 46 patients original U.S. Government Laura Bryant1*, Dong Li1*, Samuel G. Cox2, Dylan Marchione3, Evan F. Joiner4, Khadija Wilson3, Works. Distributed 3 5 1 1 6 6 under a Creative Kevin Janssen , Pearl Lee , Michael E. March , Divya Nair , Elliott Sherr , Brieana Fregeau , Commons Attribution 7 7 8 9 Klaas J. Wierenga , Alexandrea Wadley , Grazia M. S. Mancini , Nina Powell-Hamilton , NonCommercial 10 11 12 12 13 Jiddeke van de Kamp , Theresa Grebe , John Dean , Alison Ross , Heather P. Crawford , License 4.0 (CC BY-NC). Zoe Powis14, Megan T. Cho15, Marcia C. Willing16, Linda Manwaring16, Rachel Schot8, Caroline Nava17,18, Alexandra Afenjar19, Davor Lessel20,21, Matias Wagner22,23,24, Thomas Klopstock25,26,27, Juliane Winkelmann22,24,27,28, Claudia B. Catarino25, Kyle Retterer15, Jane L. Schuette29, Jeffrey W. Innis29, Amy Pizzino30,31, Sabine Lüttgen32, Jonas Denecke32, 22,24 15 3 30,31 Tim M. Strom , Kristin G. Monaghan ; DDD Study, Zuo-Fei Yuan , Holly Dubbs , Downloaded from Renee Bend33, Jennifer A.