Genomic Mapping of the MHC Transactivator CIITA Using An
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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. -
Abnormal Developmental Control of Replication-Timing Domains in Pediatric Acute Lymphoblastic Leukemia
Downloaded from genome.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Research Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia Tyrone Ryba,1,6 Dana Battaglia,1,6 Bill H. Chang,2 James W. Shirley,1 Quinton Buckley,1 Benjamin D. Pope,1 Meenakshi Devidas,3 Brian J. Druker,4,5 and David M. Gilbert1,7 1Department of Biological Science, Florida State University, Tallahassee, Florida 32306, USA; 2Division of Hematology and Oncology, Department of Pediatrics, and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, USA; 3COG and Department of Biostatistics, College of Medicine, University of Florida, Gainesville, Florida 32601, USA; 4Division of Hematology and Medical Oncology, and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, USA; 5Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication-timing profiles for pediatric leukemias from 17 patients and three cell lines, as well as normal B and T cells. Nonleukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication- timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than nonleukemic controls. Some differences were patient specific, while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, dif- ferences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication- timing domains that distinguish normal cell types. -
Hepatitis C Virus As a Unique Human Model Disease to Define
viruses Review Hepatitis C Virus as a Unique Human Model Disease to Define Differences in the Transcriptional Landscape of T Cells in Acute versus Chronic Infection David Wolski and Georg M. Lauer * Liver Center at the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA * Correspondence: [email protected]; Tel.: +1-617-724-7515 Received: 27 June 2019; Accepted: 23 July 2019; Published: 26 July 2019 Abstract: The hepatitis C virus is unique among chronic viral infections in that an acute outcome with complete viral elimination is observed in a minority of infected patients. This unique feature allows direct comparison of successful immune responses with those that fail in the setting of the same human infection. Here we review how this scenario can be used to achieve better understanding of transcriptional regulation of T-cell differentiation. Specifically, we discuss results from a study comparing transcriptional profiles of hepatitis C virus (HCV)-specific CD8 T-cells during early HCV infection between patients that do and do not control and eliminate HCV. Identification of early gene expression differences in key T-cell differentiation molecules as well as clearly distinct transcriptional networks related to cell metabolism and nucleosomal regulation reveal novel insights into the development of exhausted and memory T-cells. With additional transcriptional studies of HCV-specific CD4 and CD8 T-cells in different stages of infection currently underway, we expect HCV infection to become a valuable model disease to study human immunity to viruses. Keywords: viral hepatitis; hepatitis C virus; T cells; transcriptional regulation; transcription factors; metabolism; nucleosome 1. -
ZEB1-Induced LINC01559 Expedites Cell Proliferation, Migration
Shen et al. Cell Death and Disease (2021) 12:349 https://doi.org/10.1038/s41419-021-03571-5 Cell Death & Disease ARTICLE Open Access ZEB1-induced LINC01559 expedites cell proliferation, migration and EMT process in gastric cancer through recruiting IGF2BP2 to stabilize ZEB1 expression Huojian Shen1, Hongyi Zhu1, Yuanwen Chen1, Zhiyong Shen1, Weiqing Qiu1, Changlin Qian1 and Jie Zhang1 Abstract Gastric cancer (GC) is a common type of tumor that is characterized with high metastatic rate. In recent years, increasing studies have indicated that lncRNAs are involved in the regulation on cancer cell proliferation and migration. However, the functional role of long intergenic non-protein coding RNA 1559 (LINC01559) in GC is still unclear. In this study, we applied quantitative real-time polymerase chain reaction (RT-qPCR) and examined that LINC01559 expression was significantly enhanced in GC cells. Functional assays such as EdU, colony formation, JC-1 and transwell assays displayed that silencing LINC01559 inhibited cell proliferation and migration while promoted cell apoptosis in GC. Besides, western blot analysis and immunofluorescence assays examined the expression of factors related to epithelial- mesenchymal transition (EMT) and indicated that EMT process was blocked by LINC01559 knockdown in GC cells. Besides, LINC01559 silencing inhibited tumor growth in vivo. In addition, Chromatin immunoprecipitation (ChIP) assays demonstrated that zinc finger E-box binding homeobox 1 (ZEB1) served as a transcription factor to combine with 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; LINC01559 promoter and activated the expression of LINC01559 in GC cells. In return, LINC01559 recruited insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) to stabilize ZEB1 mRNA to up-regulate ZEB1 in GC cells. -
What Your Genome Doesn't Tell
UC San Diego UC San Diego Electronic Theses and Dissertations Title Multi-layered epigenetic control of T cell fate decisions Permalink https://escholarship.org/uc/item/8rs7c7b3 Author Yu, Bingfei Publication Date 2018 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA SAN DIEGO Multi-layered epigenetic control of T cell fate decisions A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biology by Bingfei Yu Committee in charge: Professor Ananda Goldrath, Chair Professor John Chang Professor Stephen Hedrick Professor Cornelis Murre Professor Wei Wang 2018 Copyright Bingfei Yu, 2018 All rights reserved. The dissertation of Bingfei Yu is approved, and it is ac- ceptable in quality and form for publication on microfilm and electronically: Chair University of California San Diego 2018 iii DEDICATION To my parents who have been giving me countless love, trust and support to make me who I am. iv EPIGRAPH Stay hungary. Stay foolish. | Steve Jobs quoted from the back cover of the 1974 edition of the Whole Earth Catalog v TABLE OF CONTENTS Signature Page.................................. iii Dedication..................................... iv Epigraph.....................................v Table of Contents................................. vi List of Figures.................................. ix Acknowledgements................................x Vita........................................ xii Abstract of -
Original Article Regulation of Gene Expression in HBV- and HCV-Related Hepatocellular Carcinoma: Integrated GWRS and GWGS Analyses
Int J Clin Exp Med 2014;7(11):4038-4050 www.ijcem.com /ISSN:1940-5901/IJCEM0002458 Original Article Regulation of gene expression in HBV- and HCV-related hepatocellular carcinoma: integrated GWRS and GWGS analyses Xu Zhou*, Hua-Qiang Zhu*, Jun Lu Department of General Surgery, Provincial Hospital Affiliated to Shandong University, Ji’nan 250014, China. *Equal contributors and co-first authors. Received September 11, 2014; Accepted November 8, 2014; Epub November 15, 2014; Published November 30, 2014 Abstract: Objectives: To explore the molecular mechanism of hepatitis B virus-related and hepatitis C virus-related hepatocellular carcinoma, samples from hepatitis B virus and hepatitis C virus infected patients and the normal were compared, respectively. Methods: In both experiments, genes with high value were selected based on a ge- nome-wide relative significance and genome-wide global significance model. Co-expression network of the selected genes was constructed, and transcription factors in the network were identified. Molecular complex detection al- gorithm was used to obtain sub-networks. Results: Based on the new model, the top 300 genes were selected. Co-expression network was constructed and transcription factors were identified. We obtained two common genes FCN2 and CXCL14, and two common transcription factors RFX5 and EZH2. In hepatitis B virus experiment, cluster 1 and 3 had the higher value. In cluster 1, ten of the 17 genes and one transcription factor were all reported associ- ated with hepatocellular carcinoma. In cluster 3, transcription factor ESR1 was reported related with hepatocellular carcinoma. In hepatitis C virus experiment, the value of cluster 3 and 4 was higher. -
Dynamic Regulatory Module Networks for Inference of Cell Type
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.18.210328; this version posted July 19, 2020. 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. Dynamic regulatory module networks for inference of cell type specific transcriptional networks Alireza Fotuhi Siahpirani1,2,+, Deborah Chasman1,8,+, Morten Seirup3,4, Sara Knaack1, Rupa Sridharan1,5, Ron Stewart3, James Thomson3,5,6, and Sushmita Roy1,2,7* 1Wisconsin Institute for Discovery, University of Wisconsin-Madison 2Department of Computer Sciences, University of Wisconsin-Madison 3Morgridge Institute for Research 4Molecular and Environmental Toxicology Program, University of Wisconsin-Madison 5Department of Cell and Regenerative Biology, University of Wisconsin-Madison 6Department of Molecular, Cellular, & Developmental Biology, University of California Santa Barbara 7Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison 8Present address: Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Wisconsin-Madison +These authors contributed equally. *To whom correspondence should be addressed. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.18.210328; this version posted July 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Changes in transcriptional regulatory networks can significantly alter cell fate. To gain insight into transcriptional dynamics, several studies have profiled transcriptomes and epigenomes at different stages of a developmental process. -
Generic Injuries Are Sufficient to Induce Ectopic Wnt Organizers in Hydra Jack F Cazet, Adrienne Cho, Celina E Juliano*
RESEARCH ARTICLE Generic injuries are sufficient to induce ectopic Wnt organizers in Hydra Jack F Cazet, Adrienne Cho, Celina E Juliano* Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States Abstract During whole-body regeneration, a bisection injury can trigger two different types of regeneration. To understand the transcriptional regulation underlying this adaptive response, we characterized transcript abundance and chromatin accessibility during oral and aboral regeneration in the cnidarian Hydra vulgaris. We found that the initial response to amputation at both wound sites is identical and includes widespread apoptosis and the activation of the oral-specifying Wnt signaling pathway. By 8 hr post amputation, Wnt signaling became restricted to oral regeneration. Wnt pathway genes were also upregulated in puncture wounds, and these wounds induced the formation of ectopic oral structures if pre-existing organizers were simultaneously amputated. Our work suggests that oral patterning is activated as part of a generic injury response in Hydra, and that alternative injury outcomes are dependent on signals from the surrounding tissue. Furthermore, Wnt signaling is likely part of a conserved wound response predating the split of cnidarians and bilaterians. Introduction Regeneration is an injury-induced morphogenetic process that enables the restoration of lost or damaged body parts. Although nearly all animals are capable of some form of regeneration, the greatest regenerative capacity is found in the invertebrate species capable of rebuilding their entire *For correspondence: body from small tissue fragments through a process called whole-body regeneration. In these highly [email protected] regenerative systems, amputation injuries trigger morphogenesis on both sides of the amputation plane, leading to the reconstruction of all missing body parts. -
Identification of Genetic Factors Underpinning Phenotypic Heterogeneity in Huntington’S Disease and Other Neurodegenerative Disorders
Identification of genetic factors underpinning phenotypic heterogeneity in Huntington’s disease and other neurodegenerative disorders. By Dr Davina J Hensman Moss A thesis submitted to University College London for the degree of Doctor of Philosophy Department of Neurodegenerative Disease Institute of Neurology University College London (UCL) 2020 1 I, Davina Hensman Moss confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Collaborative work is also indicated in this thesis. Signature: Date: 2 Abstract Neurodegenerative diseases including Huntington’s disease (HD), the spinocerebellar ataxias and C9orf72 associated Amyotrophic Lateral Sclerosis / Frontotemporal dementia (ALS/FTD) do not present and progress in the same way in all patients. Instead there is phenotypic variability in age at onset, progression and symptoms. Understanding this variability is not only clinically valuable, but identification of the genetic factors underpinning this variability has the potential to highlight genes and pathways which may be amenable to therapeutic manipulation, hence help find drugs for these devastating and currently incurable diseases. Identification of genetic modifiers of neurodegenerative diseases is the overarching aim of this thesis. To identify genetic variants which modify disease progression it is first necessary to have a detailed characterization of the disease and its trajectory over time. In this thesis clinical data from the TRACK-HD studies, for which I collected data as a clinical fellow, was used to study disease progression over time in HD, and give subjects a progression score for subsequent analysis. In this thesis I show blood transcriptomic signatures of HD status and stage which parallel HD brain and overlap with Alzheimer’s disease brain. -
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. -
The Human Canonical Core Histone Catalogue David Miguel Susano Pinto*, Andrew Flaus*,†
bioRxiv preprint doi: https://doi.org/10.1101/720235; this version posted July 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. The Human Canonical Core Histone Catalogue David Miguel Susano Pinto*, Andrew Flaus*,† Abstract Core histone proteins H2A, H2B, H3, and H4 are encoded by a large family of genes dis- tributed across the human genome. Canonical core histones contribute the majority of proteins to bulk chromatin packaging, and are encoded in 4 clusters by 65 coding genes comprising 17 for H2A, 18 for H2B, 15 for H3, and 15 for H4, along with at least 17 total pseudogenes. The canonical core histone genes display coding variation that gives rise to 11 H2A, 15 H2B, 4 H3, and 2 H4 unique protein isoforms. Although histone proteins are highly conserved overall, these isoforms represent a surprising and seldom recognised variation with amino acid identity as low as 77 % between canonical histone proteins of the same type. The gene sequence and protein isoform diversity also exceeds com- monly used subtype designations such as H2A.1 and H3.1, and exists in parallel with the well-known specialisation of variant histone proteins. RNA sequencing of histone transcripts shows evidence for differential expression of histone genes but the functional significance of this variation has not yet been investigated. To assist understanding of the implications of histone gene and protein diversity we have catalogued the entire human canonical core histone gene and protein complement. -
A Multiprotein Occupancy Map of the Mrnp on the 3 End of Histone
Downloaded from rnajournal.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press A multiprotein occupancy map of the mRNP on the 3′ end of histone mRNAs LIONEL BROOKS III,1 SHAWN M. LYONS,2 J. MATTHEW MAHONEY,1 JOSHUA D. WELCH,3 ZHONGLE LIU,1 WILLIAM F. MARZLUFF,2 and MICHAEL L. WHITFIELD1 1Department of Genetics, Dartmouth Geisel School of Medicine, Hanover, New Hampshire 03755, USA 2Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA 3Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27599, USA ABSTRACT The animal replication-dependent (RD) histone mRNAs are coordinately regulated with chromosome replication. The RD-histone mRNAs are the only known cellular mRNAs that are not polyadenylated. Instead, the mature transcripts end in a conserved stem– loop (SL) structure. This SL structure interacts with the stem–loop binding protein (SLBP), which is involved in all aspects of RD- histone mRNA metabolism. We used several genomic methods, including high-throughput sequencing of cross-linked immunoprecipitate (HITS-CLIP) to analyze the RNA-binding landscape of SLBP. SLBP was not bound to any RNAs other than histone mRNAs. We performed bioinformatic analyses of the HITS-CLIP data that included (i) clustering genes by sequencing read coverage using CVCA, (ii) mapping the bound RNA fragment termini, and (iii) mapping cross-linking induced mutation sites (CIMS) using CLIP-PyL software. These analyses allowed us to identify specific sites of molecular contact between SLBP and its RD-histone mRNA ligands. We performed in vitro crosslinking assays to refine the CIMS mapping and found that uracils one and three in the loop of the histone mRNA SL preferentially crosslink to SLBP, whereas uracil two in the loop preferentially crosslinks to a separate component, likely the 3′hExo.