A Comprehensive Bioinformatics Analysis to Identify a Candidate Prognostic Biomarker for Ovarian Cancer
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PARSANA-DISSERTATION-2020.Pdf
DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks. -
Supplemental Information
Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig. -
Differential Expression of ZWINT in Cancers of the Breast
Differential expression of ZW10 interacting kinetochore protein in cancers of the breast. Shahan Mamoor, MS1 [email protected] East Islip, NY 11730 Breast cancer affects women at relatively high frequency1. We mined published microarray datasets2,3 to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding the ZW10 interacting kinetochore protein, ZWINT, when comparing primary tumors of the breast to the tissue of origin, the normal breast. ZWINT was also differentially expressed in the tumor cells of patients with triple negative breast cancer. ZWINT mRNA was present at significantly higher quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of ZWINT in primary tumors of the breast was correlated with overall survival in patients with basal and luminal A subtype cancer, but in a contrary manner, demonstrating a complex relationship between correlation of primary tumor expression with overall survival based on molecular subtype. ZWINT may be of relevance to initiation, maintenance or progression of cancers of the female breast. Keywords: breast cancer, ZWINT, ZW10 interacting kinetochore protein, systems biology of breast cancer, targeted therapeutics in breast cancer. 1 Invasive breast cancer is diagnosed in over a quarter of a million women in the United States each year1 and in 2018, breast cancer was the leading cause of cancer death in women worldwide4. While patients with localized breast cancer are provided a 99% 5-year survival rate, patients with regional breast cancer, cancer that has spread to lymph nodes or nearby structures, are provided an 86% 5-year survival rate5,6. -
32-5283: Recombinant Human ZW10 Interacting Kinetochore Protein
9853 Pacific Heights Blvd. Suite D. San Diego, CA 92121, USA Tel: 858-263-4982 Email: [email protected] 32-5283: Recombinant Human ZW10 Interacting Kinetochore Protein Alternative ZW10 Interacting Kinetochore Protein,ZWINT,ZW10 Interactor,HZwint-1,KNTC2AP,ZWINT1,Human ZW10 Name : Interacting Protein-1,ZW10 Interactor Kinetochore Protein zwint-1,Zwint-1,ZW10-Interacting Protein 1. Description Source : Escherichia Coli. ZWINT Human Recombinant produced in E.coli is a single, non-glycosylated polypeptide chain containing 253 amino acids (1-230) and having a molecular mass of 27.9 kDa (Molecular size on SDS-PAGE will appear higher).ZWINT is fused to a 23 amino acid His-tag at N-terminus & purified by proprietary chromatographic techniques. ZW10 Interacting Kinetochore Protein (ZWINT) is involved in kinetochore function. ZWINT is part of the MIS12 complex, which is essential for kinetochore formation and spindle checkpoint activity. ZWINT is localized to the cytoplasm during interphase and to kinetochores from late prophase to anaphase. ZWINT interacts with ZW10 (Zeste White 10) and regulates the association between ZW10 and kinetochores. ZWINT gene defects are linked with the pathogenesis of Roberts's syndrome, an autosomal recessive disorder characterized by growth retardation due to premature chromosome separation. Product Info Amount : 10 µg Purification : Greater than 85.0% as determined by SDS-PAGE. The ZWINT solution (0.25mg/ml) contains 20mM Tris-HCl buffer (pH 8.0), 0.15M NaCl, 20% Content : glycerol and 1mM DTT. Store at 4°C if entire vial will be used within 2-4 weeks. Store, frozen at -20°C for longer periods of Storage condition : time. -
Biological Role and Disease Impact of Copy Number Variation in Complex Disease
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2014 Biological Role and Disease Impact of Copy Number Variation in Complex Disease Joseph Glessner 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 Glessner, Joseph, "Biological Role and Disease Impact of Copy Number Variation in Complex Disease" (2014). Publicly Accessible Penn Dissertations. 1286. https://repository.upenn.edu/edissertations/1286 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1286 For more information, please contact [email protected]. Biological Role and Disease Impact of Copy Number Variation in Complex Disease Abstract In the human genome, DNA variants give rise to a variety of complex phenotypes. Ranging from single base mutations to copy number variations (CNVs), many of these variants are neutral in selection and disease etiology, making difficult the detection of true common orar r e frequency disease-causing mutations. However, allele frequency comparisons in cases, controls, and families may reveal disease associations. Single nucleotide polymorphism (SNP) arrays and exome sequencing are popular assays for genome-wide variant identification. oT limit bias between samples, uniform testing is crucial, including standardized platform versions and sample processing. Bases occupy single points while copy variants occupy segments. -
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. -
ZWINT Antibody (Monoclonal) (M04) Mouse Monoclonal Antibody Raised Against a Full-Length Recombinant ZWINT
10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 ZWINT Antibody (monoclonal) (M04) Mouse monoclonal antibody raised against a full-length recombinant ZWINT. Catalog # AT4652a Specification ZWINT Antibody (monoclonal) (M04) - Product Information Application WB, E Primary Accession O95229 Other Accession BC020979 Reactivity Human Host mouse Clonality Monoclonal Isotype IgG1 Kappa Calculated MW 31293 ZWINT Antibody (monoclonal) (M04) - Additional Information Antibody Reactive Against Recombinant Protein.Western Blot detection against Gene ID 11130 Immunogen (56.21 KDa) . Other Names ZW10 interactor, ZW10-interacting protein 1, Zwint-1, ZWINT Target/Specificity ZWINT (AAH20979, 1 a.a. ~ 277 a.a) full-length recombinant protein with GST tag. MW of the GST tag alone is 26 KDa. Dilution WB~~1:500~1000 Format Clear, colorless solution in phosphate buffered saline, pH 7.2 . ZWINT monoclonal antibody (M04), clone 1B7. Western Blot analysis of ZWINT Storage expression in K-562 ( (Cat # AT4652a ) Store at -20°C or lower. Aliquot to avoid repeated freezing and thawing. Precautions ZWINT Antibody (monoclonal) (M04) is for research use only and not for use in diagnostic or therapeutic procedures. ZWINT Antibody (monoclonal) (M04) - Protocols Detection limit for recombinant GST tagged Page 1/2 10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 Provided below are standard protocols that you ZWINT is 0.03 ng/ml as a capture antibody. may find useful for product applications. • Western Blot ZWINT Antibody (monoclonal) (M04) - • Blocking Peptides Background • Dot Blot • Immunohistochemistry This gene encodes a protein that is clearly • Immunofluorescence involved in kinetochore function although an • Immunoprecipitation exact role is not known. -
Supplementary Data
Supplemental figures Supplemental figure 1: Tumor sample selection. A total of 98 thymic tumor specimens were stored in Memorial Sloan-Kettering Cancer Center tumor banks during the study period. 64 cases corresponded to previously untreated tumors, which were resected upfront after diagnosis. Adjuvant treatment was delivered in 7 patients (radiotherapy in 4 cases, cyclophosphamide- doxorubicin-vincristine (CAV) chemotherapy in 3 cases). 34 tumors were resected after induction treatment, consisting of chemotherapy in 16 patients (cyclophosphamide-doxorubicin- cisplatin (CAP) in 11 cases, cisplatin-etoposide (PE) in 3 cases, cisplatin-etoposide-ifosfamide (VIP) in 1 case, and cisplatin-docetaxel in 1 case), in radiotherapy (45 Gy) in 1 patient, and in sequential chemoradiation (CAP followed by a 45 Gy-radiotherapy) in 1 patient. Among these 34 patients, 6 received adjuvant radiotherapy. 1 Supplemental Figure 2: Amino acid alignments of KIT H697 in the human protein and related orthologs, using (A) the Homologene database (exons 14 and 15), and (B) the UCSC Genome Browser database (exon 14). Residue H697 is highlighted with red boxes. Both alignments indicate that residue H697 is highly conserved. 2 Supplemental Figure 3: Direct comparison of the genomic profiles of thymic squamous cell carcinomas (n=7) and lung primary squamous cell carcinomas (n=6). (A) Unsupervised clustering analysis. Gains are indicated in red, and losses in green, by genomic position along the 22 chromosomes. (B) Genomic profiles and recurrent copy number alterations in thymic carcinomas and lung squamous cell carcinomas. Gains are indicated in red, and losses in blue. 3 Supplemental Methods Mutational profiling The exonic regions of interest (NCBI Human Genome Build 36.1) were broken into amplicons of 500 bp or less, and specific primers were designed using Primer 3 (on the World Wide Web for general users and for biologist programmers (see Supplemental Table 2) [1]. -
Kops Research 2015 Tromer
GBE Widespread Recurrent Patterns of Rapid Repeat Evolution in the Kinetochore Scaffold KNL1 Eelco Tromer1,2,3, Berend Snel3,*,y, and Geert J.P.L. Kops1,2,4,*,y 1Molecular Cancer Research, University Medical Center Utrecht, The Netherlands 2Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands 3Theoretical Biology and Bioinformatics, Department of Biology, Faculty of Science, Utrecht University, The Netherlands 4Cancer Genomics Netherlands, University Medical Center Utrecht, The Netherlands *Corresponding author: E-mail: [email protected]; [email protected]. yThese authors contributed equally to this work. Accepted: July 22, 2015 Abstract The outer kinetochore protein scaffold KNL1 is essential for error-free chromosome segregation during mitosis and meiosis. A critical feature of KNL1 is an array of repeats containing MELT-like motifs. When phosphorylated, these motifs form docking sites for the BUB1–BUB3 dimer that regulates chromosome biorientation and the spindle assembly checkpoint. KNL1 homologs are strikingly different in both the amount and sequence of repeats they harbor. We used sensitive repeat discovery and evolutionary reconstruc- tion to show that the KNL1 repeat arrays have undergone extensive, often species-specific array reorganization through iterative cycles of higher order multiplication in conjunction with rapid sequence diversification. The number of repeats per array ranges from none in flowering plants up to approximately 35–40 in drosophilids. Remarkably, closely related drosophilid species have indepen- dently expanded specific repeats, indicating near complete array replacement after only approximately 25–40 Myr of evolution. We further show that repeat sequences were altered by the parallel emergence/loss of various short linear motifs, including phosphosites, which supplement the MELT-like motif, signifying modular repeat evolution. -
Hec1 Sequentially Recruits Zwint-1 and ZW10 to Kinetochores for Faithful Chromosome Segregation and Spindle Checkpoint Control
Oncogene (2006) 25, 6901–6914 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE Hec1 sequentially recruits Zwint-1 and ZW10 to kinetochores for faithful chromosome segregation and spindle checkpoint control Y-T Lin1,2, Y Chen2,GWu1 and W-H Lee1 1Department of Biological Chemistry, University of California, Irvine, CA, USA and 2Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA Faithful chromosome segregation is essential for main- Introduction taining the genomic integrity, which requires coordination among chromosomes, kinetochores, centrosomes and Accurate chromosome segregation is essential for spindles during mitosis. Previously, we discovered a novel maintaining the integrity of genome. In eukaryotic cells, coiled-coil protein, highly expressed in cancer 1 (Hec1), this process is precisely controlled by coordination which is indispensable for this process. However, the among the centrosomes, spindles, kinetochores and precise underlying mechanism remains unclear. Here, we chromosomes during the M phase progression. If the show that Hec1 directly interacts with human ZW10 process goes awry, chromosome segregation in indivi- interacting protein (Zwint-1), a binding partner of Zeste dual cellswill proceed with poor fidelity and the cellscan White 10 (ZW10) that is required for chromosome gain or lose the whole chromosomes. Such cells will motility and spindle checkpoint control. In mitotic cells, either die or survive with aneuploidy. Surviving cells will Hec1 transiently forms complexes with Zwint-1 and ultimately proliferate without a proper regulation and ZW10 in a temporal and spatial manner. Although the progressively accumulate more gross chromosomal three proteins have variable cell cycle-dependent expres- abnormalitiesto form a tumor (Zhou et al., 1998; sion profiles, they can only be co-immunoprecipitated Dobles et al., 2000; Fodde et al., 2001; Kaplan et al., during M phase. -
Genome-Wide Expression Profiling of Glioblastoma Using a Large
www.nature.com/scientificreports OPEN Genome-wide expression profling of glioblastoma using a large combined cohort Received: 31 May 2018 Jing Tang1,2, Dian He2,3, Pingrong Yang2,3, Junquan He2,3 & Yang Zhang 1,2 Accepted: 24 September 2018 Glioblastomas (GBMs), are the most common intrinsic brain tumors in adults and are almost universally Published: xx xx xxxx fatal. Despite the progresses made in surgery, chemotherapy, and radiation over the past decades, the prognosis of patients with GBM remained poor and the average survival time of patients sufering from GBM was still short. Discovering robust gene signatures toward better understanding of the complex molecular mechanisms leading to GBM is an important prerequisite to the identifcation of novel and more efective therapeutic strategies. Herein, a comprehensive study of genome-scale mRNA expression data by combining GBM and normal tissue samples from 48 studies was performed. The 147 robust gene signatures were identifed to be signifcantly diferential expression between GBM and normal samples, among which 100 (68%) genes were reported to be closely associated with GBM in previous publications. Moreover, function annotation analysis based on these 147 robust DEGs showed certain deregulated gene expression programs (e.g., cell cycle, immune response and p53 signaling pathway) were associated with GBM development, and PPI network analysis revealed three novel hub genes (RFC4, ZWINT and TYMS) play important role in GBM development. Furthermore, survival analysis based on the TCGA GBM data demonstrated 38 robust DEGs signifcantly afect the prognosis of GBM in OS (p < 0.05). These fndings provided new insights into molecular mechanisms underlying GBM and suggested the 38 robust DEGs could be potential targets for the diagnosis and treatment. -
New Insights on Human Essential Genes Based on Integrated Multi
bioRxiv preprint doi: https://doi.org/10.1101/260224; this version posted February 5, 2018. 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. New insights on human essential genes based on integrated multi- omics analysis Hebing Chen1,2, Zhuo Zhang1,2, Shuai Jiang 1,2, Ruijiang Li1, Wanying Li1, Hao Li1,* and Xiaochen Bo1,* 1Beijing Institute of Radiation Medicine, Beijing 100850, China. 2 Co-first author *Correspondence: [email protected]; [email protected] Abstract Essential genes are those whose functions govern critical processes that sustain life in the organism. Comprehensive understanding of human essential genes could enable breakthroughs in biology and medicine. Recently, there has been a rapid proliferation of technologies for identifying and investigating the functions of human essential genes. Here, according to gene essentiality, we present a global analysis for comprehensively and systematically elucidating the genetic and regulatory characteristics of human essential genes. We explain why these genes are essential from the genomic, epigenomic, and proteomic perspectives, and we discuss their evolutionary and embryonic developmental properties. Importantly, we find that essential human genes can be used as markers to guide cancer treatment. We have developed an interactive web server, the Human Essential Genes Interactive Analysis Platform (HEGIAP) (http://sysomics.com/HEGIAP/), which integrates abundant analytical tools to give a global, multidimensional interpretation of gene essentiality. bioRxiv preprint doi: https://doi.org/10.1101/260224; this version posted February 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.