Expression and Function of ZEB1 in the Cornea
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The Title of the Dissertation
UNIVERSITY OF CALIFORNIA SAN DIEGO Novel network-based integrated analyses of multi-omics data reveal new insights into CD8+ T cell differentiation and mouse embryogenesis A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioinformatics and Systems Biology by Kai Zhang Committee in charge: Professor Wei Wang, Chair Professor Pavel Arkadjevich Pevzner, Co-Chair Professor Vineet Bafna Professor Cornelis Murre Professor Bing Ren 2018 Copyright Kai Zhang, 2018 All rights reserved. The dissertation of Kai Zhang is approved, and it is accept- able in quality and form for publication on microfilm and electronically: Co-Chair Chair University of California San Diego 2018 iii EPIGRAPH The only true wisdom is in knowing you know nothing. —Socrates iv TABLE OF CONTENTS Signature Page ....................................... iii Epigraph ........................................... iv Table of Contents ...................................... v List of Figures ........................................ viii List of Tables ........................................ ix Acknowledgements ..................................... x Vita ............................................. xi Abstract of the Dissertation ................................. xii Chapter 1 General introduction ............................ 1 1.1 The applications of graph theory in bioinformatics ......... 1 1.2 Leveraging graphs to conduct integrated analyses .......... 4 1.3 References .............................. 6 Chapter 2 Systematic -
VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation
VSX1 Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation Luigi Bisceglia,1 Marilena Ciaschetti,2 Patrizia De Bonis,1 Pablo Alberto Perafan Campo,2 Costantina Pizzicoli,3 Costanza Scala,1 Michele Grifa,1 Pio Ciavarella,1 Nicola Delle Noci,3 Filippo Vaira,4 Claudio Macaluso,5 and Leopoldo Zelante1 PURPOSE. Keratoconus is a noninflammatory corneal disorder Most cases of keratoconus appear to be sporadic, but a that is clinically and genetically heterogeneous. Mutations in positive family history has been documented in 6% to 10% of the VSX1 (visual system homeobox 1) gene have been identi- patients.5 Both recessive and dominant patterns of inheritance fied for two distinct, inherited corneal dystrophies: posterior have been described.6–8 Autosomal dominant inheritance has polymorphous corneal dystrophy and keratoconus. To evalu- more frequently been reported in families, showing incom- ate the possible role of the VSX1 gene in a series of Italian plete penetrance and variable expressivity. Subtle videokerato- patients, 80 keratoconus-affected subjects were screened for graphic anomalies have been reported among relatives of pa- mutations. tients with keratoconus, allowing the detection of low- ETHODS expressivity forms of keratoconus, usually referred to as M . The diagnosis of keratoconus was made on the basis 9–11 of clinical examination and corneal topography. The whole subclinical or forme fruste keratoconus. Multifactorial in- heritance and a major gene model have also been pro- coding region and the exon–intron junctions of the VSX1 gene 12,13 were analyzed by direct sequencing. posed. In some cases nongenetic causes have been postu- lated, such as eye rubbing or rigid contact lens wear, which RESULTS. -
Cytoplasmic Mineralocorticoid Receptor Expression Predicts
ANTICANCER RESEARCH 39 : 5879-5890 (2019) doi:10.21873/anticanres.13792 Cytoplasmic Mineralocorticoid Receptor Expression Predicts Dismal Local Relapse-free Survival in Non-triple-negative Breast Cancer ANNIINA JÄÄSKELÄINEN 1,2 , ARJA JUKKOLA 3, KIRSI-MARIA HAAPASAARI 2, PÄIVI AUVINEN 4, YLERMI SOINI 2,5 and PEETER KARIHTALA 1 1Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; 2Department of Pathology, Medical Research Center, Oulu University Hospital, Oulu, Finland; 3Department of Oncology, Tampere University Hospital, Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland; 4Department of Oncology and Cancer Center, Kuopio University Hospital, and Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 5Department of Pathology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland Abstract. Background/Aim: The aim of the study was to predictor of local recurrence in non-metastatic breast cancer investigate the prognostic role of androgen receptor (AR), patients with non-TNBC tumour phenotype. mineralocorticoid receptor (MR) and glucocorticoid receptor β ( GR β) expression in HER-2 negative breast cancer The expression of oestrogen (ER) and progesterone receptors patients. Materials and Methods: The study population (PR) and amplification of human epidermal growth factor (n=152) was enriched with triple-negative breast cancers receptor 2 (HER2) are important prognostic and predictive (TNBC) (n=96; 63.2%). The median follow-up time was 100 factors in breast cancer (1). Moreover, androgen receptor months. AR, MR and GR β immunocytochemical staining was (AR), mineralocorticoid receptor (MR) and glucocorticoid compared with that of epithelial-mesenchymal transition receptor β ( GR β) belong to the nuclear receptor superfamily (EMT) markers (vimentin, SIP1, ZEB1). -
Computational Analysis of the Mesenchymal Signature Landscape in Gliomas Orieta Celiku1†, Anita Tandle1†, Joon-Yong Chung2, Stephen M
Celiku et al. BMC Medical Genomics (2017) 10:13 DOI 10.1186/s12920-017-0252-7 RESEARCH ARTICLE Open Access Computational analysis of the mesenchymal signature landscape in gliomas Orieta Celiku1†, Anita Tandle1†, Joon-Yong Chung2, Stephen M. Hewitt2, Kevin Camphausen1 and Uma Shankavaram1* Abstract Background: Epithelial to mesenchymal transition, and mimicking processes, contribute to cancer invasion and metastasis, and are known to be responsible for resistance to various therapeutic agents in many cancers. While a number of studies have proposed molecular signatures that characterize the spectrum of such transition, more work is needed to understand how the mesenchymal signature (MS) is regulated in non-epithelial cancers like gliomas, to identify markers with the most prognostic significance, and potential for therapeutic targeting. Results: Computational analysis of 275 glioma samples from “TheCancerGenomeAtlas” was used to identify the regulatory changes between low grade gliomas with little expression of MS, and high grade glioblastomas with high expression of MS. TF (transcription factor)-gene regulatory networks were constructed for each of the cohorts, and 5 major pathways and 118 transcription factors were identified as involved in the differential regulation of the networks. The most significant pathway - Extracellular matrix organization - was further analyzed for prognostic relevance. A 20-gene signature was identified as having prognostic significance (HR (hazard ratio) 3.2, 95% CI (confidence interval) = 1.53–8.33), after controlling for known prognostic factors (age, and glioma grade). The signature’ssignificancewasvalidatedinanindependentdataset.TheputativestemcellmarkerCD44 was biologically validated in glioma cell lines and brain tissue samples. Conclusions: Our results suggest that the differences between low grade gliomas and high grade glioblastoma are associated with differential expression of the signature genes, raising the possibility that targeting these genes might prolong survival in glioma patients. -
KLF4 Induces Mesenchymal-Epithelial Transition (MET)
bioRxiv preprint doi: https://doi.org/10.1101/2021.08.26.457621; this version posted August 27, 2021. 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. KLF4 induces Mesenchymal - Epithelial Transition (MET) by suppressing multiple EMT-inducing transcription factors Running title: KLF4 induces mesenchymal-epithelial transition (MET) Ayalur Raghu Subbalakshmi1, Sarthak Sahoo1, Isabelle McMullen2, Aaditya Narayan Saxena3, Sudhanva Kalasapura Venugopal, Jason Somarelli2,4*, Mohit Kumar Jolly1* 1 Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India 2 Department of Medicine, Duke University, Durham, NC, United States 3 Department of Biotechnology, Indian Institute of Technology, Kharagpur, India 4 Duke Cancer Institute, Duke University, Durham, NC, United States Authors to whom correspondence to be addressed: [email protected] (J.A.S), [email protected] (M.K.J.) Abstract Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs) – TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, FOXC2 – are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2, GRHL1/2). Here, using mechanism-based mathematical modeling, we show that the transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote phenotypic shift toward a more epithelial state, an observation suggested by negative correlation of KLF4 with EMT-TFs and with transcriptomic based EMT scoring metrics in cancer cell lines. -
Testicular Orphan Receptor 4 (TR4) Is a Marker for Metastasis and Poor Prognosis in Non-Small Cell Lung Cancer That Drives the EMT Phenotype
Lung Cancer 89 (2015) 320–328 Contents lists available at ScienceDirect Lung Cancer journal homepage: www.elsevier.com/locate/lungcan Testicular orphan receptor 4 (TR4) is a marker for metastasis and poor prognosis in non-small cell lung cancer that drives the EMT phenotype Liyi Zhang a,1, Jianzhi Zhang a,1, Yuanyuan Ma a,1, Jinfeng Chen a, Bin Dong b, Wei Zhao c, Xing Wang a, Qinfeng Zheng a, Fang Fang a, Yue Yang a,∗ a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Beijing, People’s Republic of China b Central Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China c Department of Cell Biology, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China article info abstract Article history: Objectives: Aberrant expression of testicular orphan receptor 4 (TR4) has been shown to regulate biological Received 11 December 2014 processes near solid tumors. However, the role of TR4 in non-small cell lung cancer (NSCLC) patient Received in revised form 30 May 2015 prognosis and the development of NSCLC cancer cells are unclear. Accepted 11 June 2015 Methods: Immunohistochemical analysis was used to evaluate the correlation between TR4 expression and clinicopathological characteristics in 291 cases of NSCLC specimens. A knockdown and overex- Keywords: pression of TR4 was performed to assess the role of TR4. Transwell and colony formation assays were Testicular orphan receptor 4 completed to investigate the metastatic and proliferative abilities. Quantitative real-time PCR, Western NSCLC Prognosis blotting and immunofluorescence staining were carried out to analyze the epithelial-to-mesenchymal Metastasis transition (EMT) phenotype. -
Whole Exome Sequencing in Families at High Risk for Hodgkin Lymphoma: Identification of a Predisposing Mutation in the KDR Gene
Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 2Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 3Ad - vanced Biomedical Computing Center, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Frederick, MD; 4Westat, Inc., Rockville MD; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; and 6Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA ©2016 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.135475 Received: August 19, 2015. Accepted: January 7, 2016. Pre-published: June 13, 2016. Correspondence: [email protected] Supplemental Author Information: NCI DCEG Cancer Sequencing Working Group: Mark H. Greene, Allan Hildesheim, Nan Hu, Maria Theresa Landi, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, Xiaohong R. Yang, Guoqin Yu NCI DCEG Cancer Genomics Research Laboratory: Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A. -
Mouse Mutants As Models for Congenital Retinal Disorders
Experimental Eye Research 81 (2005) 503–512 www.elsevier.com/locate/yexer Review Mouse mutants as models for congenital retinal disorders Claudia Dalke*, Jochen Graw GSF-National Research Center for Environment and Health, Institute of Developmental Genetics, D-85764 Neuherberg, Germany Received 1 February 2005; accepted in revised form 1 June 2005 Available online 18 July 2005 Abstract Animal models provide a valuable tool for investigating the genetic basis and the pathophysiology of human diseases, and to evaluate therapeutic treatments. To study congenital retinal disorders, mouse mutants have become the most important model organism. Here we review some mouse models, which are related to hereditary disorders (mostly congenital) including retinitis pigmentosa, Leber’s congenital amaurosis, macular disorders and optic atrophy. q 2005 Elsevier Ltd. All rights reserved. Keywords: animal model; retina; mouse; gene mutation; retinal degeneration 1. Introduction Although mouse models are a good tool to investigate retinal disorders, one should keep in mind that the mouse Mice suffering from hereditary eye defects (and in retina is somehow different from a human retina, particular from retinal degenerations) have been collected particularly with respect to the number and distribution of since decades (Keeler, 1924). They allow the study of the photoreceptor cells. The mouse as a nocturnal animal molecular and histological development of retinal degener- has a retina dominated by rods; in contrast, cones are small ations and to characterize the genetic basis underlying in size and represent only 3–5% of the photoreceptors. Mice retinal dysfunction and degeneration. The recent progress of do not form cone-rich areas like the human fovea. -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in -
Differentiation of Human Embryonic Stem Cells Into Cone Photoreceptors
© 2015. Published by The Company of Biologists Ltd | Development (2015) 142, 3294-3306 doi:10.1242/dev.125385 RESEARCH ARTICLE STEM CELLS AND REGENERATION Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling Shufeng Zhou1,*, Anthony Flamier1,*, Mohamed Abdouh1, Nicolas Tétreault1, Andrea Barabino1, Shashi Wadhwa2 and Gilbert Bernier1,3,4,‡ ABSTRACT replacement therapy may stop disease progression or restore visual Cone photoreceptors are required for color discrimination and high- function. However, a reliable and abundant source of human cone resolution central vision and are lost in macular degenerations, cone photoreceptors is not currently available. This limitation may be and cone/rod dystrophies. Cone transplantation could represent a overcome using embryonic stem cells (ESCs). ESCs originate from therapeutic solution. However, an abundant source of human cones the inner cell mass of the blastocyst and represent the most primitive remains difficult to obtain. Work performed in model organisms stem cells. Human ESCs (hESCs) can develop into cells and tissues suggests that anterior neural cell fate is induced ‘by default’ if BMP, of the three primary germ layers and be expanded indefinitely TGFβ and Wnt activities are blocked, and that photoreceptor genesis (Reubinoff et al., 2000; Thomson et al., 1998). operates through an S-cone default pathway. We report here that Work performed in amphibians and chick suggests that primordial Coco (Dand5), a member of the Cerberus gene family, is expressed cells adopt a neural fate in the absence of alternative cues (Muñoz- in the developing and adult mouse retina. Upon exposure Sanjuán and Brivanlou, 2002). -
A Three-Dimensional Organoid Model Recapitulates Tumorigenic Aspects
www.nature.com/scientificreports OPEN A three-dimensional organoid model recapitulates tumorigenic aspects and drug responses of Received: 22 June 2018 Accepted: 10 October 2018 advanced human retinoblastoma Published: xx xx xxxx Duangporn Saengwimol1, Duangnate Rojanaporn2, Vijender Chaitankar3, Pamorn Chittavanich4, Rangsima Aroonroch5, Tatpong Boontawon4, Weerin Thammachote4, Natini Jinawath4, Suradej Hongeng6 & Rossukon Kaewkhaw4 Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene and protein expression of the parental tissue. Cone signal circuitry (M/L+ cells) and glial tumor microenvironment (GFAP+ cells) were primarily present in organoids. Topotecan alone or the combined drug regimen of topotecan and melphalan efectively targeted proliferative tumor cones (RXRγ+ Ki67+) in organoids after 24-h drug exposure, blocking mitotic entry. In contrast, methotrexate showed the least efcacy against tumor cells. The drug responses of organoids were consistent with those of tumor cells in advanced disease. Patient-derived organoids enable the creation of a faithful model to use in examining novel therapeutics for RB. Retinoblastoma (RB) is a serious childhood retinal tumor that, if lef untreated, can cause death within 1–2 years. -
Alterations in Gene Expression During Sexual Differentiation in Androgen Receptor Knockout Mice Induced by Environmental Endocrine Disruptors
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 35: 399-404, 2015 Alterations in gene expression during sexual differentiation in androgen receptor knockout mice induced by environmental endocrine disruptors DEHONG LIU1,2, LIPING SHEN1, YONGLIN TAO3, YING KUANG4, LEI CAI4, DAN WANG5, MEIDUO HE3, XUEBO TONG1, SHUGUANG ZHOU1, JIE SUN1, CHENCHEN SHI3, CHUNXIAO WANG1 and YI WU1 1Department of Pediatric Surgery, Ruijin Hospital, 2Department of Pediatric Surgery, Ruijin Hospital North, 3Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025; 4Shanghai Research Center for Model Organisms, Shanghai 201203; 5School of Life Science, Shanghai University, Shanghai 200444, P.R. China Received April 4, 2014; Accepted November 13, 2014 DOI: 10.3892/ijmm.2014.2015 Abstract. In the present study, we aimed to explore the effect heterozygous and wild-type male mice offspring during sexual of environmental endocrine disruptors (EEDs) on sexual differentiation, but has no effect on homozygous offspring. differentiation in androgen receptor (AR)-/-, AR+/- and AR+/+ Therefore, EEDs play an important role during the third stage male mice. By using a Cre-loxP conditional knockout strategy, of sexual differentiation. we generated AR knockout mice. By mating flox-AR female mice with AR-Cre male mice, the offspring male mice which Introduction were produced were examined. Mice not subjected to any type of intervention were used as the controls. Furthermore, male Endocrine disruption has become a critical issue in environ- mice of different genotypes were selected and further divided mental science, particularly after the endocrine-disrupting into subgroups as follows: the control group, bisphenol A (BPA) chemical pollution accident in Taiwan which attracted public group and the D binding protein (DBP) group.