Quantitative Proteomics Screen Identifies a Substrate Repertoire Of
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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. -
Hepatocyte Growth Factor Activator Inhibitor Type 1 (Hai-1/Spint1) Is a Suppressor of Intestinal Tumorigenesis
Author Manuscript Published OnlineFirst on February 27, 2013; DOI: 10.1158/0008-5472.CAN-12-3337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hepatocyte growth factor activator inhibitor type 1 (Hai-1/Spint1) is a suppressor of intestinal tumorigenesis Shinri Hoshiko,*,# Makiko Kawaguchi,* Tsuyoshi Fukushima,* Yukihiro Haruyama,* Kenji Yorita,* Hiroyuki Tanaka,* Motoharu Seiki,‡ Haruhiko Inatsu,# Kazuo Kitamura# and Hiroaki Kataoka* *Section of Oncopathology and Regenerative Biology, Department of Pathology and #Section of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; ‡Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. S.H. and M.K. contributed equally to this study Running title: HAI-1 suppresses intestinal tumorigenesis Key words: HAI-1, carcinogenesis, colon cancer, hepatocyte growth factor, epithelial integrity Financial support: This work was supported by Grant-in-Aid for Scientific Research no. 24390099 (H.K.) and no. 23790250 (M.K.) from the Ministry of Education, Science, Sports and Culture, Japan. Corresponding author: Hiroaki Kataoka, Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Phone, +81-985-852809; Fax, +81-985-856003; E-mail, [email protected] 1 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 27, 2013; DOI: 10.1158/0008-5472.CAN-12-3337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
SPINT1) by Transcription Published: Xx Xx Xxxx Factor CDX2 E
www.nature.com/scientificreports OPEN Intestinal regulation of suppression of tumorigenicity 14 (ST14) and serine peptidase inhibitor, Kunitz Received: 5 April 2018 Accepted: 23 July 2018 type -1 (SPINT1) by transcription Published: xx xx xxxx factor CDX2 E. Thomas Danielsen 1,2, Anders Krüger Olsen2, Mehmet Coskun3, Annika W. Nonboe2, Sylvester Larsen 1,4, Katja Dahlgaard1, Eric Paul Bennett5, Cathy Mitchelmore1, Lotte Katrine Vogel2 & Jesper Thorvald Troelsen 1 The type II membrane-anchored serine protease, matriptase, encoded by suppression of tumorgenicity-14 (ST14) regulates the integrity of the intestinal epithelial barrier in concert with its inhibitor, HAI-1 encoded by serine peptidase inhibitor, Kunitz type -1 (SPINT1). The balance of the protease/inhibitor gene expression ratio is vital in preventing the oncogenic potential of matriptase. The intestinal cell lineage is regulated by a transcriptional regulatory network where the tumor suppressor, Caudal homeobox 2 (CDX2) is considered to be an intestinal master transcription factor. In this study, we show that CDX2 has a dual function in regulating both ST14 and SPINT1, gene expression in intestinal cells. We fnd that CDX2 is not required for the basal ST14 and SPINT1 gene expression; however changes in CDX2 expression afects the ST14/SPINT1 mRNA ratio. Exploring CDX2 ChIP-seq data from intestinal cell lines, we identifed genomic CDX2-enriched enhancer elements for both ST14 and SPINT1, which regulate their corresponding gene promoter activity. We show that CDX2 displays both repressive and enhancing regulatory abilities in a cell specifc manner. Together, these data reveal new insight into transcriptional mechanisms controlling the intestinal matriptase/inhibitor balance. -
SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy
SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Zhang, Huadi. 2017. SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061511 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy A dissertation presented by Huadi Zhang to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts August 2017 © 2017 Huadi Zhang All rights reserved. Dissertation Advisor: Professor David Pellman Huadi Zhang SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy Abstract Oncogenic transformation is often accompanied by chromosome instability, an increased rate of chromosome missegregation. The consequent gain or loss of chromosomes—termed aneuploidy—hinders the growth of most non-cancerous tissues, but is prevalent in tumors. During tumorigenesis, aneuploidy contributes to cellular heterogeneity and may promote downstream mutations, including chromosome rearrangements and oncogene amplification. Cellular mechanisms that safeguard against aneuploidy remain unclear. The Hippo pathway is a tumor-suppressor mechanism with essential roles in regulating tissue homeostasis. -
Research2007herschkowitzetvolume Al
Open Access Research2007HerschkowitzetVolume al. 8, Issue 5, Article R76 Identification of conserved gene expression features between comment murine mammary carcinoma models and human breast tumors Jason I Herschkowitz¤*†, Karl Simin¤‡, Victor J Weigman§, Igor Mikaelian¶, Jerry Usary*¥, Zhiyuan Hu*¥, Karen E Rasmussen*¥, Laundette P Jones#, Shahin Assefnia#, Subhashini Chandrasekharan¥, Michael G Backlund†, Yuzhi Yin#, Andrey I Khramtsov**, Roy Bastein††, John Quackenbush††, Robert I Glazer#, Powel H Brown‡‡, Jeffrey E Green§§, Levy Kopelovich, reviews Priscilla A Furth#, Juan P Palazzo, Olufunmilayo I Olopade, Philip S Bernard††, Gary A Churchill¶, Terry Van Dyke*¥ and Charles M Perou*¥ Addresses: *Lineberger Comprehensive Cancer Center. †Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. ‡Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. reports §Department of Biology and Program in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. ¶The Jackson Laboratory, Bar Harbor, ME 04609, USA. ¥Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. #Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA. **Department of Pathology, University of Chicago, Chicago, IL 60637, USA. ††Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. ‡‡Baylor College of Medicine, Houston, TX 77030, USA. §§Transgenic Oncogenesis Group, Laboratory of Cancer Biology and Genetics. Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, MD 20892, USA. Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, IL 60637, USA. -
ST14 Gene Variant and Decreased Matriptase Protein Expression Predict Poor Breast Cancer Survival
Published OnlineFirst August 17, 2010; DOI: 10.1158/1055-9965.EPI-10-0418 Cancer Research Article Epidemiology, Biomarkers & Prevention ST14 Gene Variant and Decreased Matriptase Protein Expression Predict Poor Breast Cancer Survival Jaana M. Kauppinen1, Veli-Matti Kosma1, Ylermi Soini1, Reijo Sironen1, Minna Nissinen1, Timo K. Nykopp1, Vesa Kärjä1, Matti Eskelinen2, Vesa Kataja3, and Arto Mannermaa1 Abstract Background: Matriptase plays a role in carcinogenesis, but the role of its genetic variation or that of the hepatocyte growth factor activator inhibitor-1 (HAI-1) has not been evaluated. This study aimed to examine the genetic variation of matriptase (ST14 gene) and HAI-1 (SPINT1 gene) in breast cancer risk and prognosis, to assess matriptase and HAI-1 gene and protein expression in breast tumors, and to identify their clinico- pathologic correlations and prognostic significance. Methods: Five single nucleotide polymorphisms in ST14 and three in SPINT1 were genotyped in 470 in- vasive breast cancer cases and 446 healthy controls. Gene expression analysis was done for 40 breast cancer samples. Protein expression was assessed by immunohistochemical analyses in 377 invasive breast tumors. The statistical significance of the associations among genotypes, clinicopathologic variables, and prognosis was assessed. Results: The ST14 single nucleotide polymorphism rs704624 independently predicted breast cancer surviv- al, a poor outcome associated with the minor allele (P = 0.001; risk ratio, 2.221; 95% confidence interval, 1.382- 3.568). Moreover, ST14 gene expression levels were lower among the minor allele carriers (P = 0.009), and negative/low matriptase protein expression was independently predictive of poorer survival (P = 0.046; risk ratio, 1.554; 95% confidence interval, 1.008-2.396). -
Downloaded on 14Th December 2017 from SKCM 200E, 200 Kv, 4.5 Ma) 2 Days Before the Transplantation
Gómez-Abenza et al. Journal of Experimental & Clinical Cancer Research (2019) 38:405 https://doi.org/10.1186/s13046-019-1389-3 RESEARCH Open Access Zebrafish modeling reveals that SPINT1 regulates the aggressiveness of skin cutaneous melanoma and its crosstalk with tumor immune microenvironment Elena Gómez-Abenza1,2, Sofía Ibáñez-Molero1,2, Diana García-Moreno1,2, Inmaculada Fuentes1,2, Leonard I. Zon3,4, Maria C. Mione5, María L. Cayuela6, Chiara Gabellini1,2,7* and Victoriano Mulero1,2* Abstract Background: Skin cutaneous melanoma (SKCM) is the most lethal form of skin cancer and while incidence rates are declining for most cancers, they have been steadily rising for SKCM. Serine protease inhibitor, kunitz-type, 1 (SPINT1) is a type II transmembrane serine protease inhibitor that has been shown to be involved in the development of several types of cancer, such as squamous cell carcinoma and colorectal cancer. Methods: We used the unique advantages of the zebrafish to model the impact of Spint1a deficiency in early transformation, progression and metastatic invasion of SKCM together with in silico analysis of the occurrence and relevance of SPINT1 genetic alterations of the SKCM TCGA cohort. Results: We report here a high prevalence of SPINT1 genetic alterations in SKCM patients and their association with altered tumor immune microenvironment and poor patient survival. The zebrafish model reveals that Spint1a deficiency facilitates oncogenic transformation, regulates the tumor immune microenvironment crosstalk, accelerates the onset of SKCM and promotes metastatic invasion. Notably, Spint1a deficiency is required at both cell autonomous and non-autonomous levels to enhance invasiveness of SKCM. Conclusions: These results reveal a novel therapeutic target for SKCM. -
Gene Expression Barcode Values Reveal a Potential Link Between Parkinson's Disease and Gastric Cancer
University of Kentucky UKnowledge Internal Medicine Faculty Publications Internal Medicine 2-16-2021 Gene Expression Barcode Values Reveal a Potential Link between Parkinson's Disease and Gastric Cancer Suyan Tian First Hospital of Jilin University, China Shishun Zhao Jilin University, China Mingbo Tang First Hospital of Jilin University, China Chi Wang University of Kentucky, [email protected] Follow this and additional works at: https://uknowledge.uky.edu/internalmedicine_facpub Part of the Geriatrics Commons, Internal Medicine Commons, and the Oncology Commons Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Repository Citation Tian, Suyan; Zhao, Shishun; Tang, Mingbo; and Wang, Chi, "Gene Expression Barcode Values Reveal a Potential Link between Parkinson's Disease and Gastric Cancer" (2021). Internal Medicine Faculty Publications. 231. https://uknowledge.uky.edu/internalmedicine_facpub/231 This Article is brought to you for free and open access by the Internal Medicine at UKnowledge. It has been accepted for inclusion in Internal Medicine Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Gene Expression Barcode Values Reveal a Potential Link between Parkinson's Disease and Gastric Cancer Digital Object Identifier (DOI) https://doi.org/10.18632/aging.202623 Notes/Citation Information Published by Aging, v. 13. © 2021 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available at UKnowledge: https://uknowledge.uky.edu/internalmedicine_facpub/231 www.aging-us.com AGING 2021, Vol. -
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Robertson et al. BMC Biology (2020) 18:103 https://doi.org/10.1186/s12915-020-00826-z RESEARCH ARTICLE Open Access Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets Matthew J. Robertson1,2, Katarzyna Kent3,4,5, Nathan Tharp3,4,5, Kaori Nozawa3,5, Laura Dean3,4,5, Michelle Mathew3,4,5, Sandra L. Grimm2,6, Zhifeng Yu3,5, Christine Légaré7,8, Yoshitaka Fujihara3,5,9,10, Masahito Ikawa9, Robert Sullivan7,8, Cristian Coarfa1,2,6*, Martin M. Matzuk1,3,5,6 and Thomas X. Garcia3,4,5* Abstract Background: The development of a safe, effective, reversible, non-hormonal contraceptive method for men has been an ongoing effort for the past few decades. However, despite significant progress on elucidating the function of key proteins involved in reproduction, understanding male reproductive physiology is limited by incomplete information on the genes expressed in reproductive tissues, and no contraceptive targets have so far reached clinical trials. To advance product development, further identification of novel reproductive tract-specific genes leading to potentially druggable protein targets is imperative. Results: In this study, we expand on previous single tissue, single species studies by integrating analysis of publicly available human and mouse RNA-seq datasets whose initial published purpose was not focused on identifying male reproductive tract-specific targets. We also incorporate analysis of additional newly acquired human and mouse testis and epididymis samples to increase the number of targets identified. We detected a combined total of 1178 genes for which no previous evidence of male reproductive tract-specific expression was annotated, many of which are potentially druggable targets. -
Hepatocyte Growth Factor Activator Inhibitor Type 1 (Hai-1/Spint1) Is a Suppressor of Intestinal Tumorigenesis
Author Manuscript Published OnlineFirst on February 27, 2013; DOI: 10.1158/0008-5472.CAN-12-3337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hepatocyte growth factor activator inhibitor type 1 (Hai-1/Spint1) is a suppressor of intestinal tumorigenesis Shinri Hoshiko,*,# Makiko Kawaguchi,* Tsuyoshi Fukushima,* Yukihiro Haruyama,* Kenji Yorita,* Hiroyuki Tanaka,* Motoharu Seiki,‡ Haruhiko Inatsu,# Kazuo Kitamura# and Hiroaki Kataoka* *Section of Oncopathology and Regenerative Biology, Department of Pathology and #Section of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; ‡Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. S.H. and M.K. contributed equally to this study Running title: HAI-1 suppresses intestinal tumorigenesis Key words: HAI-1, carcinogenesis, colon cancer, hepatocyte growth factor, epithelial integrity Financial support: This work was supported by Grant-in-Aid for Scientific Research no. 24390099 (H.K.) and no. 23790250 (M.K.) from the Ministry of Education, Science, Sports and Culture, Japan. Corresponding author: Hiroaki Kataoka, Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Phone, +81-985-852809; Fax, +81-985-856003; E-mail, [email protected] 1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 27, 2013; DOI: 10.1158/0008-5472.CAN-12-3337 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
A Genomic Analysis of Rat Proteases and Protease Inhibitors
A genomic analysis of rat proteases and protease inhibitors Xose S. Puente and Carlos López-Otín Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain Send correspondence to: Carlos López-Otín Departamento de Bioquímica y Biología Molecular Facultad de Medicina, Universidad de Oviedo 33006 Oviedo-SPAIN Tel. 34-985-104201; Fax: 34-985-103564 E-mail: [email protected] Proteases perform fundamental roles in multiple biological processes and are associated with a growing number of pathological conditions that involve abnormal or deficient functions of these enzymes. The availability of the rat genome sequence has opened the possibility to perform a global analysis of the complete protease repertoire or degradome of this model organism. The rat degradome consists of at least 626 proteases and homologs, which are distributed into five catalytic classes: 24 aspartic, 160 cysteine, 192 metallo, 221 serine, and 29 threonine proteases. Overall, this distribution is similar to that of the mouse degradome, but significatively more complex than that corresponding to the human degradome composed of 561 proteases and homologs. This increased complexity of the rat protease complement mainly derives from the expansion of several gene families including placental cathepsins, testases, kallikreins and hematopoietic serine proteases, involved in reproductive or immunological functions. These protease families have also evolved differently in the rat and mouse genomes and may contribute to explain some functional differences between these two closely related species. Likewise, genomic analysis of rat protease inhibitors has shown some differences with the mouse protease inhibitor complement and the marked expansion of families of cysteine and serine protease inhibitors in rat and mouse with respect to human. -
A Grhl2-Dependent Gene Network Controls Trophoblast Branching Morphogenesis
© 2015. Published by The Company of Biologists Ltd | Development (2015) 142, 1125-1136 doi:10.1242/dev.113829 RESEARCH ARTICLE A Grhl2-dependent gene network controls trophoblast branching morphogenesis Katharina Walentin1,2, Christian Hinze1,2, Max Werth1,2,3, Nadine Haase2, Saaket Varma4, Robert Morell5, Annekatrin Aue1,2, Elisabeth Pötschke1, David Warburton4, Andong Qiu3, Jonathan Barasch3, Bettina Purfürst1, Christoph Dieterich6, Elena Popova1, Michael Bader1, Ralf Dechend2, Anne Cathrine Staff7, Zeliha Yesim Yurtdas1,8,9, Ergin Kilic10 and Kai M. Schmidt-Ott1,2,11,* ABSTRACT KEY WORDS: Placenta defects, Epithelial differentiation, Epithelial Spint1 Healthy placental development is essential for reproductive success; morphogenesis, , Basement membrane defects failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 INTRODUCTION (GRHL2), a CP2-type transcription factor, is highly expressed in The placenta facilitates the exchange of metabolites between mother chorionic trophoblast cells, including basal chorionic trophoblast (BCT) and fetus. Pregnancy-associated diseases, such as pre-eclampsia cells located at the chorioallantoic interface in murine placentas. and fetal intrauterine growth restriction (IUGR), affect up to 10% Placentas from Grhl2-deficient mouse embryos displayed defects of pregnancies. The mouse placenta is a widely used model in BCT cell polarity and basement membrane integrity at the system (Adamson et al., 2002; Georgiades et al., 2002). Fetal chorioallantoic interface, as well as a severe disruption of labyrinth trophectoderm-derived cells invade the maternal endometrium and branching morphogenesis. Selective Grhl2 inactivation only in epiblast- form the site of feto-maternal exchange, which is referred to as the derived cells rescued all placental defects but phenocopied villous tree in humans and the labyrinth in mice.