Genomics in Endocrinology Contemporary Endocrinology P. Michael Conn, S E ERIES DITOR Polycystic Ovary Syndrome: Current Contro- EarlyDiagnosisofEndocrineDiseases,editedby versies, from the Ovary to the Pancreas, ROBERTS.BAR,2003 edited by ANDREA DUNAIF, JEFFREY R. CHANG, Type I Diabetes: Etiology and Treatment, edited STEPHENFRANKS,ANDRICHARDS.LEGRO,2008 byMARKA.SPERLING,2003 TheMetabolicSyndrome:Epidemiology,Clinical Handbook of Diagnostic Endocrinology, edited Treatment, and Underlying Mechanisms, byJANETE.HALLANDLYNNETTEK.NIEMAN,2003 Pediatric Endocrinology: A Practical Clinical edited by BARBARA C. HANSEN AND GEORGE A.BRAY,2008 Guide,editedbySALLYRADOVICKANDMARGARET Genomics in Endocrinology: DNA Microarray H.MACGILLIVRAY,2003 AnalysisinEndocrineHealthandDisease, DiseasesoftheThyroid,SecondEdition,editedby edited by STUART HANDWERGER AND BRUCE J. LEWISE.BRAVERMAN,2003 DevelopmentalEndocrinology:FromResearchto ARONOW,2008 Controversies in Treating Diabetes: Clinical and ClinicalPractice,editedbyERICAA.EUGSTER Research Aspects, edited by DEREKLEROITH ANDORAHIRSCHPESCOVITZ,2002 Osteoporosis: Pathophysiology and Clinical ANDAARONI.VINIK,2007 AutoimmuneDiseasesinEndocrinology,editedby Management, edited by ERICS. ORWOLLAND ANTHONYP.WEETMAN,2007 MICHAELBLIZIOTES,2002 When Puberty is Precocious: Scientific and Challenging Cases in Endocrinology, edited by ClinicalAspects,editedbyORAH.PESCOVITZ MARKE.MOLITCH,2002 Selective Estrogen Receptor Modulators: ANDEMILYC.WALVOORD,2007 ResearchandClinicalApplications,edited Hypertension and Hormone Mechanisms, edited byROBERTM.CAREY,2007 by ANDREA MANNI AND MICHAEL F. VERDERAME, 2002 Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation Transgenics in Endocrinology, edited by MARTIN and Treatment, edited by JOHNE. NESTLER, MATZUK, CHESTER W. BROWN, AND T. RAJENDRA KUMAR,2001 EVANTHIADIAMANTI-KANDARAKIS,RENATOPASQUALI, Assisted Fertilization and Nuclear Transfer in ANDD.PANDIS,2007 Mammals, edited by DONP. WOLFANDMARY TheLeydigCellinHealthandDisease,editedby ZELINSKI-WOOTEN,2001 ANITA H. PAYNE AND MATTHEW PHILLIP HARDY, Adrenal Disorders, edited by ANDREW N.MARGIORIS 2007 ANDGEORGEP.CHROUSOS,2001 Treatment of the Obese Patient, edited by ROBERT Endocrine Oncology, edited by STEPHENP. ETHIER, F.KUSHNERANDDANIELH.BESSESEN,2007 2000 AndrogenExcessDisordersinWomen:Polycystic Endocrinology of the Lung: Development and Ovary Syndrome and Other Disorders, Surfactant Synthesis, edited by CAROLE Second Edition, edited by RICARDO AZZIS, R.MENDELSON,2000 JOHNE.NESTLER,ANDDIDIERDEWAILLY,2006 SportsEndocrinology,editedbyMICHELLEP.WARREN Evidence-Based Endocrinology, edited by VICTOR ANDNAAMAW.CONSTANTINI,2000 M.MONTORI,2006 Gene Engineering in Endocrinology, edited by Office Andrology, edited by PHILLIPE.PANTTONAND MARGARETA.SHUPNIK,2000 DAVIDE.BATTAGLIA,2005 EndocrinologyofAging,editedbyJOHNE.MORLEY Stem Cells in Endocrinology, edited by LINDAB. ANDLUCRETIAVANDENBERG,2000 LESTER,2005 HumanGrowthHormone:ResearchandClinical Male Hypogonadism: Basic, Clinical, and Practice,editedbyROYG.SMITHANDMICHAEL TherapeuticPrinciples,editedbySTEPHENJ. O.THORNER,2000 WINTERS,2004 Hormones and the Heart in Health and Disease, AndrogensinHealthandDisease,editedbyCARRIE editedbyLEONARDSHARE,1999 BAGATELLANDWILLIAMJ.BREMNER,2003 Menopause: Endocrinology and Management, Endocrine Replacement Therapy in Clinical edited by DAVID B. SEIFER AND ELIZABETH Practice,editedbyA.WAYNEMEIKLE,2003 A.KENNARD,1999 Genomics in Endocrinology DNA Microarray Analysis in Endocrine Health and Disease Edited by tuart Handwerger, md S Cincinnati Children’s Hospital Medical Center (CCHMC), University of Cincinnati College of Medicine, Cincinnati, OH, USA ruce ronow p d B J. A , h University of Cincinnati College of Medicine, Cincinnati, OH, USA Editors StuartHandwerger BruceAronow CincinnatiChildren’sHospitalMedical UniversityofCincinnatiCollegeofMedicine Center(CCHMC) Cincinnati,OH,USA UniversityofCincinnatiCollegeofMedicine 3333BurnettAvenue Cincinnati,OH45229,USA [email protected] SeriesEditor P.MichaelConn,MD DivisionofNeuroscience OregonHealthandScienceUniversity OregonNationalPrimateResearchCenter 505NW185thAve. Beaverton,OR97006,USA ISBN:978-1-58829-651-1 e-ISBN:978-1-59745-309-7 LibraryofCongressControlNumber:2007931072 ©2008HumanaPress,apartofSpringerScience+BusinessMedia,LLC Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewrittenpermissionof thepublisher(HumanaPress,999RiverviewDrive,Suite208,Totowa,NJ07512USA),exceptforbriefexcerptsin connectionwithreviewsorscholarlyanalysis.Useinconnectionwithanyformofinformationstorageandretrieval, electronicadaptation,computersoftware,orbysimilarordissimilarmethodologynowknownorhereafterdeveloped isforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyarenotidentified assuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubjecttoproprietaryrights. Coverillustration:Acompositeofacomplexgeneexpressionprofileheatmap,anetworkviewofgeneinteractions thatconstitutethemechanismsforgeneregulation,andacartoonviewofendocrineandparacrinerelationshipswithin andbetweendifferentendocrinetissuesandsomatictissuesrespondingtoendocrinehormones.Theheatmapdepicts clustersofgenes(inrows)thatarecoordinatelyactivated(red)orrepressed(blue)indifferenttissuesandasafunction ofdifferentinfluences(samplesandtreatmentsareincolumnsacrossthemap)suchasbydifferentcombinationsof hormonalagents.(CourtesyofMikeZenderandBruceAronow.) Printedonacid-freepaper 987654321 springer.com Preface Duringthelastfiveyears,thedevelopmentofnewtechnologiescapableofmonitoring genome function has gone from hopeful estimates to very solid depictions of genome output from individual samples. The application of this technology to the fields of endocrinologyhasresultedinnewinsightsaswellastherecognitionthatrefinementsin biological sampling, technology, experimentation, and data analysis and interpretation will yield a wealth of new understandings. In this volume, forty-five plus authors have contributed descriptions of a variety of investigations that reflect the beginnings of an integrated understanding of how different biological systems respond to endocrine signals.Thedevelopmentandapplicationoffocusedstudiesthatcanrevealthemecha- nisms of endocrine action is a major and exciting challenge. Endocrine actions are divided over a broad range of mechanisms that encompass development, homeostasis, reproduction,andenvironmentaladaptivenessofcells,tissues,systems,andorganisms. Givenadequateexperimentaldesignandanalysis,geneexpressionprofilingcanprovide considerable insight into endocrine system functions, responses, and interactions. In our introductory chapter, we describe several issues in hypothesis formulation, experimentaldesign,dataanalysis,andfollow-upstudiesthatmaycorroborate,validate, and extend hypotheses gained through microarray analyses. The contributed chapters spanavarietyofapplicationsthatwehavedividedintotheareasof(1)genomicinsights into molecular mechanisms responsible for hormone action, (2) genomic characteri- zations of endocrine producing tissues, and (3) genomic manifestations of diseases of hormonal systems. We thank all of the authors for their efforts in summarizing some of their current understandingsandtothemembersofourdepartmentsandinstitutionwhohaveshown patience and provided support for our efforts. We would also like to thank Humana Press for their enthusiasm on this project, and Allene Ford and Nancy Fehr for their invaluable assistance. Stuart Handwerger Bruce J. Aronow v Contents Preface..................................................... v Contributors................................................ ix Part I Introduction 1 Microarray-based Gene Expression Analysis of Endocrine Systems: Principles of Experimental Design and Interpretation Anil G. Jegga, DVM, Bruce J. Aronow, PhD, and Stuart Handwerger, MD.............................. 3 Part II Hormone Action and Molecular Mechanisms 2 Gene Expression Profiles and Transcription Factors Involved in Parathyroid Hormone Signaling in Osteoblastic Cells Ling Qin, PhD, Ping Qiu, PhD, and Nicola C. Partridge, PhD........................................... 25 3 Analysis of Growth Hormone Effects on Hepatic Gene Expression in Hypophysectomized Rats Amilcar Flores-Morales, PhD and Leandro Fernández-Pérez, MD, PhD....................... 41 4 Gene Expression Profiling in Leiomyoma in Response to GnRH Therapy and TGF-(cid:2) Nasser Chegini, PhD and Xiaoping Luo, MD................. 67 5 Gene Profiling Analysis of Androgen Receptor Mediated Function Clay E. S. Comstock, PhD, Craig J. Burd, PhD, Walter J. Jessen, PhD, and Karen E. Knudsen, PhD......... 83 6 Interrogating Estrogen Receptor (cid:3) Signaling in Breast Cancer by Chromatin Immunoprecipitation Microarrays Alfred S. L. Cheng, PhD, Huey-Jen L. Lin, PhD, and Tim H. -M. Huang, PhD.............................. 115 7 Gene Expression Analysis of the Adrenal Cortex in Health and Disease Anelia Horvath, PhD and Constantine A. Stratakis, MD, DMedSci................................................. 131 Part III Endocrine Producing Tissues 8 DNA Microarray Analysis of Human Uterine Decidualization Ori Eyal, MD and Stuart Handwerger, MD.................. 147 vii viii Contents 9 Large-scale DNA Microarray Data Analysis Reveals Glucocorticoid Receptor-mediated Breast Cancer Cell Survival Pathways Min Zou, PhD, Wei Wu, MD, PhD, and Suzanne D. Conzen, MD.............................. 165 10 Application of Microarrays for Gene Transcript Analysis in Type 2 Diabetes R. Sreekumar, PhD, C. P. Kolbert, MS, Y. Asmann, PhD, and K. S. Nair, MD, PhD................................. 185 11 DNA Microarray Analysis of Effects of TSH, Iodide, Cytokines, and Therapeutic Agents on Gene Expression in Cultured Human Thyroid Follicles Kanji Sato, MD, PhD, Kazuko Yamazaki, BS, and Emiko Yamada, MD.................................. 207 Part IV Diseases of Hormonal Systems 12 Genomics and Polycystic Ovary Syndrome (PCOS): The Use of Microarray Analysis to Identify New Candidate Genes Jennifer R. Wood, PhD and Jerome F. Strauss III, MD, PhD... 219 13 Microarray Analysis of Alterations Induced by Obesity in White Adipose Tissue Gene Expression Profiling Julien Tirard, Ricardo Moraes, Danielle Naville, PhD, and Martine Bégeot, PhD................................. 239 14 Novel Molecular Signaling and Classification of Human Clinically Nonfunctioning Pituitary Adenomas Identified by Microarray and Reverse Transcription-Quantitative Polymerase Chain Reaction Chheng-Orn Evans, MS, Carlos S. Moreno, PhD, and Nelson M. Oyesiku, MD, PhD, FACS .................. 263 15 Gene Expression Studies of Prostate Hyperplasia in Prolactin Transgenic Mice Karin Dillner, PhD, Jon Kindblom, MD, PhD, Amilcar Flores-Morales, PhD, and Håkan Wennbo, MD, PhD....... 271 Index.......................................................... 283 Contributors Bruce J. Aronow, phd, Division Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH Yan W. Asmann, phd, Bioinformatics Application Scientist, Mayo Clinic College of Medicine, Rochester, MN Martine Bégeot, phd, Permanent Researcher from INSERM, Lyon, France Craig J. Burd, phd, Departments of Cell Biology and Pathology, University of Cincinnati, Cincinnati, OH Nasser Chegini, phd, Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL Alfred S. L. Cheng, phd, Post-doctoral Researcher, Division of Human Cancer Genetics, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH Clay E. S. Comstock, phd, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH Suzanne D. Conzen, md, Associate Professor, Department of Medicine and The Ben May Institute of Cancer Research, The University of Chicago, Chicago, IL Karin Dillner, phd, Disease Biology, AstraZeneca R&D, Södertälje, Sweden Chheng-Orn Evans, ms, Research Supervisor, Department of Neurosurgery, Emory University, Atlanta, GA Ori Eyal, md, The Edmond and Lily Safra Children’s Hospital, The Chaim Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer, Israel Leandro Fernández-Pérez, md, phd, Associate Professor or Pharmacology, Department of Clinical Sciences, Molecular Pharmacology Group, University of Las Palmas de Gran Canaria–Canary Institute for Cancer Research, RTICCC, Canary Islands, Spain Amilcar Flores-Morales, phd, Associate Professor of Experimental Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Instututet, Karolinska Hospital, Stockholm, Sweden Stuart Handwerger, md, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH Anelia Horvath, phd, Senior Fellow, Section on Endocrinology and Genetics, (SEGEN)/DEB, NICHD, NIH, Bethesda, MD Tim H. -M. Huang, phd, Professor, Division of Human Cancer Genetics, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH ix x Contributors Anil G. Jegga, dvm, Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH Walter J. Jessen, phd, Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH Jon Kindblom, md, phd, Department of Oncology, Göteborg University, Göteborg, Sweden Karen E. Knudsen, phd, Center for Environmental Genetics and Department of Cell Biology, University of Cincinnati, Cincinnati, OH Christopher P. Kolbert, ms, Senior Research Technologist, Mayo Clinic College of Medicine, Rochester, MN Huey-Jen L. Lin, phd, Assistant Professor, Division of Medical Technology, School of Allied Medical Professions, Ohio State University, Columbus, OH Xiaoping Luo, md, Research Assistant Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL Ricardo Moraes, Post-Graduate Student, Breast Center, Baylor College of Medicine, Houston, TX Carlos S. Moreno, phd, Assistant Professor, Department of Pathology and Laboratory of Medicine and Cancer Institute, Emory University, Atlanta, GA K. Sreekumaran Nair, md, phd, David Murdock Dole Professor and Professor of Medicine, Division of Endocrinology, Mayo Clinic and Foundation, Rochester, MN Danielle Naville, phd, Permanent Researcher from INSERM, Lyon, France Nelson M. Oyesiku, md, phd, facs, Professor and Vice-Chairman, Neurological Surgery; Director, Neurosurgery Residency Program; Director, Laboratory of Molecular Neurosurgery and Biotechnology, Department of Neurological Surgery, Emory University School of Medicine; Past-President, Congress of Neurological Surgeons; Past-President, Georgia Neurosurgical Society, Atlanta, GA Nicola C. Partridge, phd, Professor and Chair, Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ Ling Qin, phd, Assistant Professor, Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ Ping Qiu, phd, Principal Scientist, Bioinformatics Group and Discovery Technology Department, Schering-Plough Research Institute, Kenwilworth, NJ Kanji Sato, md, phd, Professor, Field of Thyroid and Parathyroid Disease, Division of Internal Medicine, Graduate School of Medicine, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan Raghavakaimal Sreekumar, phd, Associate Professor of Medicine, Mayo Clinic College of Medicine, Rochester, MN Constantine A. Stratakis, md, dmedsci, Chief, Heritable Disorders Branch, NICHD, NIH; Director, Pediatric Endocrinology Training Program, NICHD, NIH; Head, Section on Endocrinology and Genetics, (SEGEN)/DEB, NICHD, NIH, Bethesda, MD Contributors xi Jerome F. Strauss III, md, phd, Executive Vice President for Medical Affairs, VCU Health System Dean, Professor of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, VA Julien Tirard, Graduate Student, INSERM, Lyon, France Hakan Wennbo, md, phd, Integrative Pharmacology, AstraZeneca R&D, Molndal, Sweden Jennifer R. Wood, phd, Assistant Professor, Department of Animal Science, University of Nebraska, Lincoln, NE Wei Wu, md, phd, Research Associate, Division of Molecular Oncology, Evanston Northwestern Healthcare Research Institute, Evanston, IL Emiko Yamada, md, Director, Thyroid Disease Institute, Kanaji Hospital, Kita-ku, Tokyo, Japan Kazuko Yamazaki, bs, Thyroid Disease Institute, Kanaji Hospital, Kita-ku, Tokyo, Japan Min Zou, phd, Post-doctoral Scholar, Department of Medicine, The University of Chicago, Chicago, IL