Volume 18 - Number 1 January 2014
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Escape from X Chromosome Inactivation Is an Intrinsic Property of the Jarid1c Locus
Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus Nan Lia,b and Laura Carrela,1 aDepartment of Biochemistry and Molecular Biology and bIntercollege Graduate Program in Genetics, Pennsylvania State College of Medicine, Hershey, PA 17033 Edited by Stanley M. Gartler, University of Washington, Seattle, WA, and approved September 23, 2008 (received for review August 8, 2008) Although most genes on one X chromosome in mammalian fe- Sequences on the X are hypothesized to propagate XCI (12) and males are silenced by X inactivation, some ‘‘escape’’ X inactivation to be depleted at escape genes (8, 9). LINE-1 repeats fit such and are expressed from both active and inactive Xs. How these predictions, particularly on the human X (8–10). Distinct dis- escape genes are transcribed from a largely inactivated chromo- tributions of other repeats classify some mouse X genes (5). some is not fully understood, but underlying genomic sequences X-linked transgenes also test the role of genomic sequences in are likely involved. We developed a transgene approach to ask escape gene expression. Most transgenes are X-inactivated, whether an escape locus is autonomous or is instead influenced by although a number escape XCI (e.g., refs. 13 and 14). Such X chromosome location. Two BACs carrying the mouse Jarid1c gene transgene studies indicate that, in addition to CTCF (6), locus and adjacent X-inactivated transcripts were randomly integrated control regions and matrix attachment sites are also not suffi- into mouse XX embryonic stem cells. Four lines with single-copy, cient to escape XCI (15, 16). -
Environmental Influences on Endothelial Gene Expression
ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community. -
Viewpoint, from the Literature, Most of the Genes in Our Sets Are Known to Be Strongly Related to Cancer
BMC Bioinformatics BioMed Central Research Open Access A voting approach to identify a small number of highly predictive genes using multiple classifiers Md Rafiul Hassan*1, M Maruf Hossain*1, James Bailey1,2, Geoff Macintyre1,2, Joshua WK Ho3,4 and Kotagiri Ramamohanarao1,2 Address: 1Department of Computer Science and Software Engineering, The University of Melbourne, Victoria 3010, Australia, 2NICTA Victoria Laboratory, The University of Melbourne, Victoria 3010, Australia, 3School of Information Technologies, The University of Sydney, NSW 2006, Australia and 4NICTA, Australian Technology Park, Eveleigh, NSW 2015, Australia Email: Md Rafiul Hassan* - [email protected]; M Maruf Hossain* - [email protected]; James Bailey - [email protected]; Geoff Macintyre - [email protected]; Joshua WK Ho - [email protected]; Kotagiri Ramamohanarao - [email protected] * Corresponding authors from The Seventh Asia Pacific Bioinformatics Conference (APBC 2009) Beijing, China. 13–16 January 2009 Published: 30 January 2009 <supplement> <title> <p>Selected papers from the Seventh Asia-Pacific Bioinformatics Conference (APBC 2009)</p> </title> <editor>Michael Q Zhang, Michael S Waterman and Xuegong Zhang</editor> <note>Research</note> </supplement> BMC Bioinformatics 2009, 10(Suppl 1):S19 doi:10.1186/1471-2105-10-S1-S19 This article is available from: http://www.biomedcentral.com/1471-2105/10/S1/S19 © 2009 Hassan 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. -
Epigenetic Reprogramming Underlies Efficacy of DNA Demethylation
www.nature.com/scientificreports OPEN Epigenetic reprogramming underlies efcacy of DNA demethylation therapy in osteosarcomas Naofumi Asano 1,2, Hideyuki Takeshima3, Satoshi Yamashita3, Hironori Takamatsu2,3, Naoko Hattori3, Takashi Kubo4, Akihiko Yoshida5, Eisuke Kobayashi6, Robert Nakayama2, Morio Matsumoto2, Masaya Nakamura2, Hitoshi Ichikawa 4, Akira Kawai6, Tadashi Kondo1 & Toshikazu Ushijima 3* Osteosarcoma (OS) patients with metastasis or recurrent tumors still sufer from poor prognosis. Studies have indicated the efcacy of DNA demethylation therapy for OS, but the underlying mechanism is still unclear. Here, we aimed to clarify the mechanism of how epigenetic therapy has therapeutic efcacy in OS. Treatment of four OS cell lines with a DNA demethylating agent, 5-aza-2′- deoxycytidine (5-aza-dC) treatment, markedly suppressed their growth, and in vivo efcacy was further confrmed using two OS xenografts. Genome-wide DNA methylation analysis showed that 10 of 28 primary OS had large numbers of methylated CpG islands while the remaining 18 OS did not, clustering together with normal tissue samples and Ewing sarcoma samples. Among the genes aberrantly methylated in primary OS, genes involved in skeletal system morphogenesis were present. Searching for methylation-silenced genes by expression microarray screening of two OS cell lines after 5-aza-dC treatment revealed that multiple tumor-suppressor and osteo/chondrogenesis-related genes were re-activated by 5-aza-dC treatment of OS cells. Simultaneous activation of multiple genes related to osteogenesis and cell proliferation, namely epigenetic reprogramming, was considered to underlie the efcacy of DNA demethylation therapy in OS. Osteosarcoma (OS) is the most common malignant tumor of the bone in children and adolescents1. -
Sex-Differential DNA Methylation and Associated Regulation Networks in Human Brain Implicated in the Sex-Biased Risks of Psychiatric Disorders
Molecular Psychiatry https://doi.org/10.1038/s41380-019-0416-2 ARTICLE Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders 1,2 1,2 1 2 3 4 4 4 Yan Xia ● Rujia Dai ● Kangli Wang ● Chuan Jiao ● Chunling Zhang ● Yuchen Xu ● Honglei Li ● Xi Jing ● 1 1,5 2 6 1,2,7 1,2,8 Yu Chen ● Yi Jiang ● Richard F. Kopp ● Gina Giase ● Chao Chen ● Chunyu Liu Received: 8 November 2018 / Revised: 18 March 2019 / Accepted: 22 March 2019 © Springer Nature Limited 2019 Abstract Many psychiatric disorders are characterized by a strong sex difference, but the mechanisms behind sex-bias are not fully understood. DNA methylation plays important roles in regulating gene expression, ultimately impacting sexually different characteristics of the human brain. Most previous literature focused on DNA methylation alone without considering the regulatory network and its contribution to sex-bias of psychiatric disorders. Since DNA methylation acts in a complex regulatory network to connect genetic and environmental factors with high-order brain functions, we investigated the 1234567890();,: 1234567890();,: regulatory networks associated with different DNA methylation and assessed their contribution to the risks of psychiatric disorders. We compiled data from 1408 postmortem brain samples in 3 collections to identify sex-differentially methylated positions (DMPs) and regions (DMRs). We identified and replicated thousands of DMPs and DMRs. The DMR genes were enriched in neuronal related pathways. We extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein–protein interaction data. -
Open Data for Differential Network Analysis in Glioma
International Journal of Molecular Sciences Article Open Data for Differential Network Analysis in Glioma , Claire Jean-Quartier * y , Fleur Jeanquartier y and Andreas Holzinger Holzinger Group HCI-KDD, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz 2/V, 8036 Graz, Austria; [email protected] (F.J.); [email protected] (A.H.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 27 October 2019; Accepted: 3 January 2020; Published: 15 January 2020 Abstract: The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes. -
Gene Silencing of TSPYL5 Mediated by Aberrant Promoter Methylation in Gastric Cancers Yeonjoo Jung1, Jinah Park1, Yung-Jue Bang1,2 and Tae-You Kim1,2
Laboratory Investigation (2008) 88, 153–160 & 2008 USCAP, Inc All rights reserved 0023-6837/08 $30.00 Gene silencing of TSPYL5 mediated by aberrant promoter methylation in gastric cancers Yeonjoo Jung1, Jinah Park1, Yung-Jue Bang1,2 and Tae-You Kim1,2 DNA methylation is crucial for normal development, but gene expression altered by DNA hypermethylation is often associated with human diseases, especially cancers. The gene TSPYL5, encoding testis-specific Y-like protein, was pre- viously identified in microarray screens for genes induced by the inhibition of DNA methylation and histone deacetylation in glioma cell lines. The TSPYL5 showed a high frequency of DNA methylation-mediated silencing in both glioma cell lines and primary glial tumors. We now report that TSPYL5 is also inactivated by DNA methylation and could be a putative epigenetic target gene in gastric cancers. We found that the expression of TSPYL5 mRNA was frequently downregulated and inversely correlated with DNA methylation in seven out of nine gastric cancer cell lines. TSPYL5 mRNA expression was also restored after treating with a DNA methyltransferase inhibitor. In primary gastric tumors, methylation-specific PCR results in 23 of the 36 (63.9%) cases revealed that the hypermethylation at CpG islands of the TSPYL5 was detectable at a high frequency. Furthermore, TSPYL5 suppressed the growth of gastric cancer cells as demonstrated by a colony for- mation assay. Thus, strong associations between TSPYL5 expression and hypermethylation were observed, and aberrant methylation at a CpG island of TSPYL5 may play an important role in development of gastric cancers. Laboratory Investigation (2008) 88, 153–160; doi:10.1038/labinvest.3700706; published online 3 December 2007 KEYWORDS: DNMT inhibitor; gastric cancer; NAP domain; promoter hypermethylation; TSPYL5 Epigenetic events are heritable modifications that regulate TSPYL6. -
Rna-Sequencing Applications: Gene Expression Quantification and Methylator Phenotype Identification
The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 8-2013 RNA-SEQUENCING APPLICATIONS: GENE EXPRESSION QUANTIFICATION AND METHYLATOR PHENOTYPE IDENTIFICATION Guoshuai Cai Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Bioinformatics Commons, Computational Biology Commons, and the Medicine and Health Sciences Commons Recommended Citation Cai, Guoshuai, "RNA-SEQUENCING APPLICATIONS: GENE EXPRESSION QUANTIFICATION AND METHYLATOR PHENOTYPE IDENTIFICATION" (2013). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 386. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/386 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. RNA-SEQUENCING APPLICATIONS: GENE EXPRESSION QUANTIFICATION AND METHYLATOR PHENOTYPE IDENTIFICATION -
Single-Nucleotide Polymorphisms in the TSPYL-4 and NT5DC1 Genes Are Associated with Susceptibility to Chronic Obstructive Pulmonary Disease
MOLECULAR MEDICINE REPORTS 6: 631-638, 2012 Single-nucleotide polymorphisms in the TSPYL-4 and NT5DC1 genes are associated with susceptibility to chronic obstructive pulmonary disease YI GUO1*, YI GONG2*, GUOCHAO SHI1, KUN YANG1, CHUNMING PAN3, MIN LI1, QINGYUN LI1, QIJIAN CHENG1, RANRAN DAI1, LIANG FAN1 and HUANYING WAN1 1Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University (SJTU), School of Medicine; 2Department of Respiratory Medicine, Huashan Hospital, Fudan University; 3Ruijin Hospital, State Key Laboratory of Medical Genomics, Molecular Medicine Center, Shanghai Jiao Tong University (SJTU), School of Medicine, Shanghai 200025, P.R. China Received February 12, 2012; Accepted June 18, 2012 DOI: 10.3892/mmr.2012.964 Abstract. The risk of developing chronic obstructive pulmo- block. We constructed the TSPYL-4 and NT5DC1 haplo- nary disease (COPD) is partially determined by genetic types of the cases and controls, but no significant difference and environmental factors. Many published candidate gene between the two groups was found. rs3749893 A allele of studies show conflicting results due to ethnic differences TSPYL-4 and rs1052443 C allele of NT5DC1 were associated and sample sizes. The number of these studies carried out in with a protective effect against the deterioration of pulmonary Chinese populations is small. To investigate candidate genes function. In conclusion, TSPYL-4 and NT5DC1 gene poly- and haplotypes for susceptibility to COPD in a southern morphisms are associated with susceptibility to COPD and Han Chinese population, we performed genotyping of DNA pulmonary function. samples in 200 COPD patients and 250 control subjects by analyzing 54 single-nucleotide polymorphisms (SNPs) in Introduction 23 genes associated with the development of COPD and/or pulmonary function identified by genome-wide association Chronic obstructive pulmonary disease (COPD) is expected studies (GWAS). -
Pan-Cancer Transcriptome Analysis Reveals a Gene Expression
Modern Pathology (2016) 29, 546–556 546 © 2016 USCAP, Inc All rights reserved 0893-3952/16 $32.00 Pan-cancer transcriptome analysis reveals a gene expression signature for the identification of tumor tissue origin Qinghua Xu1,6, Jinying Chen1,6, Shujuan Ni2,3,4,6, Cong Tan2,3,4,6, Midie Xu2,3,4, Lei Dong2,3,4, Lin Yuan5, Qifeng Wang2,3,4 and Xiang Du2,3,4 1Canhelp Genomics, Hangzhou, Zhejiang, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; 4Institute of Pathology, Fudan University, Shanghai, China and 5Pathology Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China Carcinoma of unknown primary, wherein metastatic disease is present without an identifiable primary site, accounts for ~ 3–5% of all cancer diagnoses. Despite the development of multiple diagnostic workups, the success rate of primary site identification remains low. Determining the origin of tumor tissue is, thus, an important clinical application of molecular diagnostics. Previous studies have paved the way for gene expression-based tumor type classification. In this study, we have established a comprehensive database integrating microarray- and sequencing-based gene expression profiles of 16 674 tumor samples covering 22 common human tumor types. From this pan-cancer transcriptome database, we identified a 154-gene expression signature that discriminated the origin of tumor tissue with an overall leave-one-out cross-validation accuracy of 96.5%. The 154-gene expression signature was first validated on an independent test set consisting of 9626 primary tumors, of which 97.1% of cases were correctly classified. -
A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase. -
TSPYL2 Is a Novel Regulator of SIRT1 and P300 Activity in Response to DNA Damage
ABSTRACT Sexual dimorphism has been demonstrated to play a critical role in cancer incidence and survival. The X-linked gene TSPY-Like 2 (TSPYL2) encodes for a protein that was previously reported to be involved in the regulation of cell cycle progression and DNA damage response (DDR), a complex of molecular pathways by which the cell is able to face DNA lesions that could lead to genomic instability and cancer initiation. TSPYL2 expression is known to be reduced or mutated in different kind of cancer cells, suggesting a tumor suppressor role. However, the physiological roles of TSPYL2 in both DDR and tumorigenesis are still unknown and need to be clarified. We recently found that after DNA damage TSPYL2 protein is induced in normal and cancer female cell lines, as well as in untransformed male cell lines. Conversely, TSPYL2 induction is not observed in male cancer cell lines, except for those cells that lost the Y chromosome during the oncogenic process. These results suggest that protein accumulation could be prevented by a factor encoded by the male sex specific chromosome and that TSPYL2 could have a sex specific function in the DDR. RESULTS AND CONCLUSIONS In unstressed conditions - TSPYL2 protein is kept at low levels by protein ubiquitination and proteasome mediated degradation. - Mdm2 is one of the ubiquitin ligase involved in TSPYL2 protein levels regulation. However, we cannot exclude the involvement of other ubiquitin ligases. In response to DNA damage: - TSPYL2 gene expression is induced in both normal and cancer cells by E2F1 - TSPYL2 protein accumulates in non-transformed cells and in female cancer cells - In male cancer cells, TSPYL2 protein does not accumulate except that in those cell lines that during the oncogenic process lost the Y chromosome.