Transcriptional Alterations During Mammary Tumor Progression in Mice

Total Page:16

File Type:pdf, Size:1020Kb

Transcriptional Alterations During Mammary Tumor Progression in Mice TRANSCRIPTIONAL ALTERATIONS DURING MAMMARY TUMOR PROGRESSION IN MICE AND HUMANS By Karen Fancher B.S. Hartwick College, 1995 A THESIS Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (Interdisciplinary in Functional Genomics and in Biomedical Sciences) The Graduate School The University of Maine December, 2008 Advisory Committee: Barbara B. Knowles Ph.D., Professor, The Jackson Laboratory, Co-Advisor Gary A. Churchill Ph.D., Professor, The Jackson Laboratory, Co-Advisor Keith W. Hutchison Ph.D., Professor of Biochemistry and Molecular Biology, The University of Maine, Thesis Committee Chair M. Kate Beard-Tisdale Ph.D., Professor of Spatial Information Science and Engineering, The University of Maine Shaoguang Li M.D., Ph.D., Associate Professor, The Jackson Laboratory LIBRARY RIGHTS STATEMENT In presenting this thesis in partial fulfillment of the requirements for an advanced degree at The University of Maine, I agree that the Library shall make it freely available for inspection. I further agree that permission for "fair use" copying of this thesis for scholarly purposes may be granted by the Librarian. It is understood that any copying or publication of this thesis for financial gain shall not be allowed without my written permission. Signature: Date: TRANSCRIPTIONAL ALTERATIONS DURING MAMMARY TUMOR PROGRESSION IN MICE AND HUMANS By Karen Fancher Thesis Co-Advisors: Dr. Barbara B. Knowles and Dr. Gary A. Churchill An Abstract of the Thesis Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy (Interdisciplinary in Functional Genomics and in Biomedical Sciences) December, 2008 Family history, reproductive factors, hormonal exposures, and subjective immunohisto- chemical evaluations of in situ lesions, and to a lesser extent age, remain the best clinical predictors of an individual’s risk of developing breast cancer. Identification of early markers predictive of impending invasive breast cancer from in situ carcinoma is a long-term goal. The latent mammary cancer transgenic mouse model of human breast cancer, C57BL/6J- Tg(WapTAg)1Knw (Waptag1), develops characteristic stages of tumorigenesis in a highly predictable manner: atypical hyperplasia advances to ductal carcinoma in situ (DCIS), which progresses to papillary adenocarcinomas and/or solid, invasive tumors. Microarray analyses of whole mammary glands and tumors across these stages, to detect transcriptional changes throughout tumorigenesis, revealed marked, phased stage-specific changes. In contrast, results from the laser capture microdissected tumor cells depict a moderately constant characteristic tumorigenic profile, irrespective of stage. Evaluation of differences in whole glands with those of microdissected samples suggests that paracrine signaling between tumor and stromal cells substantially alters the tumor microenvironment, early in progression. Strikingly, comparison of statistically significant microarray results between Waptag1 DCIS and human DCIS revealed 2,097 overlapping early transcriptional changes. When compared with species-specific controls, common abundant early gene alterations were associated with cell cycle, cell division, and DNA replication Gene Ontology categories, with a notable decrease in genes involved in aerobic energy metabolism, and significant increased transcription of retrotransposons and chromosome modification genes. Based on these initial experimental results, retrotransposons were identified as a potential marker for testing in several mouse models and in biopsies derived from breast cancer patients. Analysis of data from five independent mouse models of mammary cancer and five human breast cancer datasets revealed over expression of retrotransposons, mainly Class I and Class II LTR elements, as well as LINEs and SINEs, when compared with normal samples. Cross-species comparison of gene expression profiles suggests epigenetic alterations and chromatin remodeling changes coincide with retrotransposon over expression. Through validation of such mutual human and mouse changes in gene expression, these novel putative markers may allow earlier detection and therapeutic intervention, possibly reducing the incidence of invasion and metastases in patients with breast cancer. ACKNOWLEDGEMENTS The research presented in this thesis was funded by CA34196, CA88327, and CA89713 from the National Institutes of Health; National Science Foundation IGERT Program Fellowship 0221625 (KSF, BBK-PI); Maine Cancer Foundation (BBK-PI); The University of Maine Graduate School of Biomedical Sciences and The Judith A. Lese Breast Cancer Foundation, Inc. Research presented here may be part of ongoing collaborations. Karen Fancher is indebted to Drs. D. Craig Allred and Sangjun Lee for generously sharing the human DCIS raw microarray data. She would like to acknowledge the exceptional opportunities she was offered by her mentors, Drs. Barbara B. Knowles and Gary A. Churchill, during her graduate studies. She is appreciative of the efforts of her graduate committee members as well. She is abundantly grateful to Drs. Igor Mikaelian, Carol Bult, Barbara Tennent, Alexei Evsikov, and Carrie Evsikova as well as summer student, Hannah Tetrault; their support helped her to accomplish this goal. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS...............................................................................................................ii LIST OF TABLES……………………………………………………..................................................vii LIST OF FIGURES…………………………………………………...................................................viii Chapter 1. INTRODUCTION......................................................................................................................1 1.1. Tumor Progression......................................................................................................1 1.2. Human Breast Carcinogenesis ...................................................................................1 1.3. The Experimental Hypothesis......................................................................................3 1.4. Mouse Models of Mammary Cancer.............................................................................3 1.5. In Situ Carcinoma Studies In Vivo...............................................................................6 1.6. SV40 Tumor Antigen (SV40 Tag)................................................................................7 1.7. Chromatin Remodeling, Retrotransposons and Cancer............................................11 1.8. Statistical Microarray Analysis...................................................................................17 1.9. Summary…………………………………………………………………………….……….23 2. MATERIALS AND METHODS.................................................................................................24 2.1. Mice and Samples......................................................................................................24 2.1.1. Mice............................................................................................................24 2.1.2. Whole mammary tumors and glands..........................................................24 2.1.3. Cryopreserved tumors and mammary glands.............................................25 2.1.4. Laser Capture Microdissected Samples.....................................................25 2.2. Microarrays.................................................................................................................28 2.2.1. Mouse.........................................................................................................28 2.2.2. Human........................................................................................................29 2.3. Statistical Experimental Design and Analysis.............................................................29 2.3.1. NIA 15K two-color microarrays (Waptag1 only)……………………….……...30 2.3.2. Affymetrix one-color microarrays (Waptag1 or human)…………….………..30 2.3.3. Survival Analysis.........................................................................................31 iii 2.4. Retrotransposons........................................................................................................32 2.4.1. Datasets……………………………………………………………….…………….....32 2.4.1.1. Mouse Microarrays……………………………………………….……………....32 2.4.1.2. Human Two Color Microarray Data…………………………….……………....32 2.4.1.3. Human Affymetrix Data……………………………………………….………....33 2.4.2. Classification………………………………………………………………….……….33 2.5. Cross-Species Comparisons......................................................................................34 2.6. Gene Ontology and Pathway Analysis.......................................................................34 2.6.1. VisuaL Annotation Display................................................................................34 2.6.2. GenMAPP Energy Pathway Analysis................................................................35 2.6.3. MouseCyc Pathway Representation………………….........................................35 3. CHARACTERIZATION OF WAPTAG1, A MOUSE MODEL OF DUCTAL CARCINOMA IN SITU WITH PROGRESSION TO INVASIVE CANCER.................................36 3.1. Waptag1 Tumorigenesis, a Multi-Stage Progressive Disease with Delayed-Onset............................................................................................................36 3.2. Waptag1 Whole Glands and Tumors Exhibit Stage-Specific Expression Profiles.....................................................................................................37
Recommended publications
  • Astrin-SKAP Complex Reconstitution Reveals Its Kinetochore
    RESEARCH ARTICLE Astrin-SKAP complex reconstitution reveals its kinetochore interaction with microtubule-bound Ndc80 David M Kern1,2, Julie K Monda1,2†, Kuan-Chung Su1†, Elizabeth M Wilson-Kubalek3, Iain M Cheeseman1,2* 1Whitehead Institute for Biomedical Research, Cambridge, United States; 2Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; 3Department of Cell Biology, The Scripps Research Institute, La Jolla, United States Abstract Chromosome segregation requires robust interactions between the macromolecular kinetochore structure and dynamic microtubule polymers. A key outstanding question is how kinetochore-microtubule attachments are modulated to ensure that bi-oriented attachments are selectively stabilized and maintained. The Astrin-SKAP complex localizes preferentially to properly bi-oriented sister kinetochores, representing the final outer kinetochore component recruited prior to anaphase onset. Here, we reconstitute the 4-subunit Astrin-SKAP complex, including a novel MYCBP subunit. Our work demonstrates that the Astrin-SKAP complex contains separable kinetochore localization and microtubule binding domains. In addition, through cross-linking analysis in human cells and biochemical reconstitution, we show that the Astrin-SKAP complex binds synergistically to microtubules with the Ndc80 complex to form an integrated interface. We propose a model in which the Astrin-SKAP complex acts together with the Ndc80 complex to stabilize correctly formed kinetochore-microtubule interactions. *For correspondence: DOI: https://doi.org/10.7554/eLife.26866.001 [email protected] †These authors contributed equally to this work Introduction Competing interests: The The macromolecular kinetochore complex links chromosomes to dynamic microtubule polymers and authors declare that no harnesses the forces generated by microtubule growth and depolymerization to facilitate accurate competing interests exist.
    [Show full text]
  • Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice
    Loyola University Chicago Loyola eCommons Biology: Faculty Publications and Other Works Faculty Publications 2013 Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice Mihaela Palicev Gunter P. Wagner James P. Noonan Benedikt Hallgrimsson James M. Cheverud Loyola University Chicago, [email protected] Follow this and additional works at: https://ecommons.luc.edu/biology_facpubs Part of the Biology Commons Recommended Citation Palicev, M, GP Wagner, JP Noonan, B Hallgrimsson, and JM Cheverud. "Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice." Genome Biology and Evolution 5(10), 2013. This Article is brought to you for free and open access by the Faculty Publications at Loyola eCommons. It has been accepted for inclusion in Biology: Faculty Publications and Other Works by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. © Palicev et al., 2013. GBE Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice Mihaela Pavlicev1,2,*, Gu¨ nter P. Wagner3, James P. Noonan4, Benedikt Hallgrı´msson5,and James M. Cheverud6 1Konrad Lorenz Institute for Evolution and Cognition Research, Altenberg, Austria 2Department of Pediatrics, Cincinnati Children‘s Hospital Medical Center, Cincinnati, Ohio 3Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University 4Department of Genetics, Yale University School of Medicine 5Department of Cell Biology and Anatomy, The McCaig Institute for Bone and Joint Health and the Alberta Children’s Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Canada 6Department of Anatomy and Neurobiology, Washington University *Corresponding author: E-mail: [email protected].
    [Show full text]
  • ACTL6A Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells and Correlates with Poor Clinical Outcomes
    OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH ACTL6A Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells and Correlates with Poor Clinical Outcomes This article was published in the following Dove Press journal: OncoTargets and Therapy Rui-zhe Li1 Background: ACTL6A, a regulatory subunit of ATP-dependent chromatin-remodeling Yun-yun Li1,2 complexes SWI/SNF, has been identified as a central oncogenic driver in many tumor types. Hui Qin1 Materials and Methods: We used immunohistochemistry (IHC) to detect ACTL6A Shan-shan Li1 expression in esophageal squamous cell carcinoma (ESCC) tissues. Then, the effect of ACTL6A on proliferation and DNA synthesis was explored by using cell counting kit 8 1 Department of Pathology, School of (CCK8) and EdU retention assays. The potential oncogenic mechanism of ACTL6A in Basic Medical Sciences, Zhengzhou University and First Affiliated Hospital of ESCC cells was also analyzed by flow cytometry and Western blotting. We further estab­ Zhengzhou University, Zhengzhou, lished an ESCC xenograft mouse model to validate the in vitro results. Henan 450000, People’s Republic of China; 2Department of Stomatology, First Results: ACTL6A expression, localized in cancer cell nuclei, was markedly higher in ESCC Affiliated Hospital of Zhengzhou tissues than in the corresponding noncancerous tissues (P<0.001) and was positively asso­ University, Zhengzhou, Henan 450000, ciated with tumor size, histological differentiation, T stage and tumor-node-metastasis People’s Republic of China (TNM) stage. Kaplan–Meier analysis revealed that high ACTL6A expression was signifi­ cantly associated with poor overall survival (OS) (P = 0.008, HR= 2.562, 95% CI: 1.241–­ 5.289), and decision curve analysis (DCA) demonstrated that ACTL6A could increase the clinical prognostic efficiency of the original clinical prediction model.
    [Show full text]
  • S41598-021-90243-1.Pdf
    www.nature.com/scientificreports OPEN Metabolomics and computational analysis of the role of monoamine oxidase activity in delirium and SARS‑COV‑2 infection Miroslava Cuperlovic‑Culf1,2*, Emma L. Cunningham3, Hossen Teimoorinia4, Anuradha Surendra1, Xiaobei Pan5, Stefany A. L. Bennett2,6, Mijin Jung5, Bernadette McGuiness3, Anthony Peter Passmore3, David Beverland7 & Brian D. Green5* Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS‑CoV‑2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium‑ susceptibility in the postoperative setting using metabolomic profling of cerebrospinal fuid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found signifcant concentration diferences in several amino acids, acylcarnitines and polyamines linking delirium‑prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein–protein docking analysis showed that there potentially is strong binding of SARS‑CoV‑2 spike protein to MAOB. The possibility that SARS‑CoV‑2 infuences MAOB activity leading to the observed neurological and platelet‑based complications of SARS‑CoV‑2 infection requires further investigation. COVID-19 is an ongoing major global health emergency caused by severe acute respiratory syndrome coro- navirus SARS-CoV-2. Patients admitted to hospital with COVID-19 show a range of features including fever, anosmia, acute respiratory failure, kidney failure and gastrointestinal issues and the death rate of infected patients is estimated at 2.2%1.
    [Show full text]
  • Genomic Analyses Reveal Foxg As an Upstream Regulator of Wnt1 Required For
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.08.416008; this version posted December 9, 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. Genomic analyses reveal FoxG as an upstream regulator of wnt1 required for posterior identity specification in planarians E. Pascual-Carreras1, M. Marín-Barba3, S. Castillo-Lara1, P. Coronel-Córdoba1, M.S. Magri2, G.N. Wheeler3 J.F. Abril1, J.L. Gomez-Skarmeta2, E. Saló1* & T. Adell1* 1 Department of Genetics, Microbiology and Statistics, Universitat de Barcelona (UB) & Institute of Biomedicine of Universitat de Barcelona (IBUB), Barcelona, Spain. 2 Centro Andaluz de Biología del Desarollo (CABD), Universidad Pablo de Olavide, Sevilla, Spain. 3 School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, UK. *Corresponding authors: Emili Saló ([email protected]) and Teresa Adell ([email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.08.416008; this version posted December 9, 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 Embryonic specification of the first body axis requires the formation of an Organizer, a group of cells with the ability to instruct fates in the surrounding tissue. The existence of organizing regions in adults, i.e.
    [Show full text]
  • 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.
    [Show full text]
  • Location Analysis of Estrogen Receptor Target Promoters Reveals That
    Location analysis of estrogen receptor ␣ target promoters reveals that FOXA1 defines a domain of the estrogen response Jose´ e Laganie` re*†, Genevie` ve Deblois*, Ce´ line Lefebvre*, Alain R. Bataille‡, Franc¸ois Robert‡, and Vincent Gigue` re*†§ *Molecular Oncology Group, Departments of Medicine and Oncology, McGill University Health Centre, Montreal, QC, Canada H3A 1A1; †Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6; and ‡Laboratory of Chromatin and Genomic Expression, Institut de Recherches Cliniques de Montre´al, Montreal, QC, Canada H2W 1R7 Communicated by Ronald M. Evans, The Salk Institute for Biological Studies, La Jolla, CA, July 1, 2005 (received for review June 3, 2005) Nuclear receptors can activate diverse biological pathways within general absence of large scale functional data linking these putative a target cell in response to their cognate ligands, but how this binding sites with gene expression in specific cell types. compartmentalization is achieved at the level of gene regulation is Recently, chromatin immunoprecipitation (ChIP) has been used poorly understood. We used a genome-wide analysis of promoter in combination with promoter or genomic DNA microarrays to occupancy by the estrogen receptor ␣ (ER␣) in MCF-7 cells to identify loci recognized by transcription factors in a genome-wide investigate the molecular mechanisms underlying the action of manner in mammalian cells (20–24). This technology, termed 17␤-estradiol (E2) in controlling the growth of breast cancer cells. ChIP-on-chip or location analysis, can therefore be used to deter- We identified 153 promoters bound by ER␣ in the presence of E2. mine the global gene expression program that characterize the Motif-finding algorithms demonstrated that the estrogen re- action of a nuclear receptor in response to its natural ligand.
    [Show full text]
  • A Multistep Bioinformatic Approach Detects Putative Regulatory
    BMC Bioinformatics BioMed Central Research article Open Access A multistep bioinformatic approach detects putative regulatory elements in gene promoters Stefania Bortoluzzi1, Alessandro Coppe1, Andrea Bisognin1, Cinzia Pizzi2 and Gian Antonio Danieli*1 Address: 1Department of Biology, University of Padova – Via Bassi 58/B, 35131, Padova, Italy and 2Department of Information Engineering, University of Padova – Via Gradenigo 6/B, 35131, Padova, Italy Email: Stefania Bortoluzzi - [email protected]; Alessandro Coppe - [email protected]; Andrea Bisognin - [email protected]; Cinzia Pizzi - [email protected]; Gian Antonio Danieli* - [email protected] * Corresponding author Published: 18 May 2005 Received: 12 November 2004 Accepted: 18 May 2005 BMC Bioinformatics 2005, 6:121 doi:10.1186/1471-2105-6-121 This article is available from: http://www.biomedcentral.com/1471-2105/6/121 © 2005 Bortoluzzi 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. Abstract Background: Searching for approximate patterns in large promoter sequences frequently produces an exceedingly high numbers of results. Our aim was to exploit biological knowledge for definition of a sheltered search space and of appropriate search parameters, in order to develop a method for identification of a tractable number of sequence motifs. Results: Novel software (COOP) was developed for extraction of sequence motifs, based on clustering of exact or approximate patterns according to the frequency of their overlapping occurrences.
    [Show full text]
  • Regulation of Oxidized Base Damage Repair by Chromatin Assembly Factor 1 Subunit a Chunying Yang1,*,†, Shiladitya Sengupta1,2,*,†, Pavana M
    Published online 27 October 2016 Nucleic Acids Research, 2017, Vol. 45, No. 2 739–748 doi: 10.1093/nar/gkw1024 Regulation of oxidized base damage repair by chromatin assembly factor 1 subunit A Chunying Yang1,*,†, Shiladitya Sengupta1,2,*,†, Pavana M. Hegde1,JoyMitra1, Shuai Jiang3, Brooke Holey3, Altaf H. Sarker3, Miaw-Sheue Tsai3, Muralidhar L. Hegde1,2,4 and Sankar Mitra1,2,* 1Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA, 2Weill Cornell Medical College, Cornell University, New York, NY 10065, USA, 3Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA and 4Houston Methodist Neurological Institute, Houston, TX 77030, USA Received March 23, 2016; Revised October 13, 2016; Editorial Decision October 17, 2016; Accepted October 19, 2016 ABSTRACT INTRODUCTION Reactive oxygen species (ROS), generated both en- ROS, continuously generated in mammalian cells both en- dogenously and in response to exogenous stress, in- dogenously and by environmental genotoxicants, induce duce point mutations by mis-replication of oxidized various genomic lesions, including oxidized bases, abasic bases and other lesions in the genome. Repair of (AP) sites and single-strand breaks (SSBs). If unrepaired or these lesions via base excision repair (BER) pathway mis-repaired, DNA lesions would cause mutations which may lead to cytotoxicity and cell death and also carcino- maintains genomic fidelity. Regulation of the BER genic transformation (1). The base excision repair (BER) pathway for mutagenic oxidized bases, initiated by pathway, responsible for repair of oxidized base lesions NEIL1 and other DNA glycosylases at the chromatin which contribute to drug/radiation sensitivity is highly con- level remains unexplored.
    [Show full text]
  • A Genomic Approach to Study Down Syndrome and Cancer Inverse Comorbidity: Untangling the Chromosome 21
    PERSPECTIVE ARTICLE published: 04 February 2015 doi: 10.3389/fphys.2015.00010 A genomic approach to study down syndrome and cancer inverse comorbidity: untangling the chromosome 21 Jaume Forés-Martos , Raimundo Cervera-Vidal , Enrique Chirivella , Alberto Ramos-Jarero and Joan Climent* Genomics and Systems Biology (InGSB) Lab, Oncology and Hematology Department, Biomedical Research Institute INCLIVA, Valencia, Spain Edited by: Down syndrome (DS), one of the most common birth defects and the most widespread Anaïs Baudot, Centre National de la genetic cause of intellectual disabilities, is caused by extra genetic material on Recherche Scientifique, France chromosome 21 (HSA21). The increased genomic dosage of trisomy 21 is thought to Reviewed by: be responsible for the distinct DS phenotypes, including an increased risk of developing Cristian Bellodi, Lund University, Sweden some types of childhood leukemia and germ cell tumors. Patients with DS, however, have Jian-Hua Mao, Lawrence Berkeley a strikingly lower incidence of many other solid tumors. We hypothesized that the third National Laboratory, USA copy of genes located in HSA21 may have an important role on the protective effect *Correspondence: that DS patients show against most types of solid tumors. Focusing on Copy Number Joan Climent, Genomics and Variation (CNV) array data, we have generated frequencies of deleted regions in HSA21 in Systems Biology (InGSB) Lab, Oncology and Hematology four different tumor types from which DS patients have been reported to be protected. Department, Biomedical Research We describe three different regions of deletion pointing to a set of candidate genes Institute INCLIVA, Avda Blasco that could explain the inverse comorbidity phenomenon between DS and solid tumors.
    [Show full text]
  • Increased ACTL6A Occupancy Within Mswi/SNF Chromatin Remodelers
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.22.435873; this version posted March 22, 2021. 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. Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma Chiung-Ying Chang1,2,7, Zohar Shipony3,7, Ann Kuo1,2, Kyle M. Loh4,5, William J. Greenleaf3,6, Gerald R. Crabtree1,2,5* 1Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA. 2Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. 3Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. 4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. 5Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA. 6Department of Applied Physics, Stanford University, Stanford, California 94305, USA. 7These authors contributed equally. *Corresponding author: Gerald R. Crabtree, [email protected] Summary Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit, ACTL6A, is amplified at an early stage in the development of squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives its interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was sub-stoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near-saturation of ACTL6A within BAF complexes.
    [Show full text]
  • Epigenetic Mechanisms of Lncrnas Binding to Protein in Carcinogenesis
    cancers Review Epigenetic Mechanisms of LncRNAs Binding to Protein in Carcinogenesis Tae-Jin Shin, Kang-Hoon Lee and Je-Yoel Cho * Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul 08826, Korea; [email protected] (T.-J.S.); [email protected] (K.-H.L.) * Correspondence: [email protected]; Tel.: +82-02-800-1268 Received: 21 September 2020; Accepted: 9 October 2020; Published: 11 October 2020 Simple Summary: The functional analysis of lncRNA, which has recently been investigated in various fields of biological research, is critical to understanding the delicate control of cells and the occurrence of diseases. The interaction between proteins and lncRNA, which has been found to be a major mechanism, has been reported to play an important role in cancer development and progress. This review thus organized the lncRNAs and related proteins involved in the cancer process, from carcinogenesis to metastasis and resistance to chemotherapy, to better understand cancer and to further develop new treatments for it. This will provide a new perspective on clinical cancer diagnosis, prognosis, and treatment. Abstract: Epigenetic dysregulation is an important feature for cancer initiation and progression. Long non-coding RNAs (lncRNAs) are transcripts that stably present as RNA forms with no translated protein and have lengths larger than 200 nucleotides. LncRNA can epigenetically regulate either oncogenes or tumor suppressor genes. Nowadays, the combined research of lncRNA plus protein analysis is gaining more attention. LncRNA controls gene expression directly by binding to transcription factors of target genes and indirectly by complexing with other proteins to bind to target proteins and cause protein degradation, reduced protein stability, or interference with the binding of other proteins.
    [Show full text]