Human Epigenomics PDF
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Human Epigenomics Carsten Carlberg · Ferdinand Molnár Human Epigenomics CarstenCarlberg FerdinandMolnár InstituteofBiomedicine InstituteofBiomedicine UniversityofEasternFinland UniversityofEasternFinland Kuopio Kuopio Finland Finland ISBN 978-981-10-7613-8 ISBN 978-981-10-7614-5 (eBook) https://doi.org/10.1007/978-981-10-7614-5 LibraryofCongressControlNumber:2018932160 ©SpringerNatureSingaporePteLtd.2018 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof thematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recita- tion,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinfor- mation storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodologynowknownorhereafterdeveloped. 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The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Preface The term “epigenetics” was first introduced 75 years ago by Conrad Waddington and is used since then, in order to describe regulatory and information storing mechanisms of specific genes that do not involve any change of their DNA sequence. Epigenetics is closely related to the extensively folded state, in which the genome is packaged, known as chromatin. New genomic tools, which have been developed since the sequencing of the human genome, nowadays allow the genome-wide assessment of, for example, chromatin states and DNA modifica- tions, and led to the discovery of unexpected new epigenetic principles, such as epigenomic memory. This was the start of the field of “epigenomics,” the relation ofwhichtohumanhealthanddiseaseisdiscussedinthistextbook. This book aims to summarize, in a condensed form, the role of epigenomics in defining chromatin states that are representative of active genes (euchromatin) and repressedgenes(heterochromatin).Moreover,thisbookdiscussestheprinciplesof gene regulation, chromatin stability, genomic imprinting and the reversibility of DNA methylation and histone modifications. This information should enable a betterunderstandingof celltypeidentities andwillprovidenew directionsfor stu- dies of, for example, (i) cellular reprograming, (ii) the response of chromatin to environmental signals and (iii) epigenetic therapies that can improve or restore humanhealth. Theshiftfromepigeneticstoepigenomics,i.e.froma“singlegene”toa“genome- wide” view, significantly enhances the understanding of chromatin accessibility, 3-dimensional(3D)organizationofthegenomeanditsconsequencesongeneexpres- sionaffectingthephenotypeandfunctionofcells.Thisbookwilldiscussthecentral importanceofepigenomicsduringembryogenesisandcellulardifferentiationaswell asintheprocessofagingandtheriskforthedevelopmentofcancer.Moreover,the roleoftheepigenomeasa molecularstorage ofcellularevents notonlyinthe brain butalsointheimmunesystemandinmetabolicorganswillbedescribed. Over the last decade the terms “epigenetics”/”epigenomics” raised interest not only in biomedicine, such as oncology or nutritional sciences, but also in fields that do not routinely address genetics, such as ecology, physiology and psychol- ogy. Some scientists primarily use the term epigenomics to explain changes in v vi Preface gene expression, while others employ the term, in order to refer to transgenera- tional effects and/or inherited gene expression states. This book aims on to clarify the principles of epigenomics and may be used as a basis for the different disci- plines implementing it. For this reason not only biochemists should be aware of theconceptsofepigenomics,butallstudentsofbiologyandmedicinewouldbene- fit from being familiar with this topic. Thus, a solid understanding of the epigen- omeshouldbeafundamentalgoalofmodernlifescienceresearchandteaching. The content of the book is based on the lecture course “Molecular Medicine and Genetics” that is given by one of us (C. Carlberg) in different forms since 2002 at the University of Eastern Finland in Kuopio. Thematically, this book is located between our textbooks “Mechanisms of Gene Regulation” (ISBN 978-94- 017-7741-4) and “Nutrigenomics” (ISBN 978-3-319-30415-1), studying of which may also be interesting to our readers. The book is sub-divided into three sections and13chapters.FollowingtheIntroduction(sectionA),sectionBwillexplainthe molecular basis of epigenomics, while section C will provide examples for the impact of epigenomics in human health and disease. The lecture course is primar- ily designed for Master level students of biomedicine, but is also frequented by PhD students as well as by students of other bioscience disciplines. The course andhencethistextbookhasfourmajorlearningobjectives.Studentsshould: 1. have detailed understanding of the molecular elements of epigenomics, suchas chromatin organization, chemical modifications found in DNA and histones andthenuclearproteinsmediatingandcoordinatingthesereactions, 2. recognize the key components, mechanisms and processes in epigenomics and the multiple layers of its regulatory complexity in processes, such as cellular differentiation, aging and cancer, and its function in the brain, immune system andmetabolicorgans, 3. show the ability to analyze the impact of DNA methylation, histone modifica- tionsand3Dchromatinorganizationforhumanhealthanddisease,and 4. apply knowledge in epigenomics in designing, performing and analyzing respectiveexperiments,suchasChIP-seq,ATAC-seqandsingle-cellRNA-seq. We hope the readers will enjoy this rather visual book and get as enthusiastic aboutepigenomicsastheauthorsare. October2017 CarstenCarlberg Kuopio FerdinandMolnár Acknowledgements The authors would like to thank Reinhard Bornemann, MD, DrPH, PhD, for extensiveproofreadingandconstructivecriticism. vii List of Abbreviations 3C chromosomeconformationcapture 3D 3-dimensional 5caC 5-carboxylcytosine 5fC 5-formylcytosine 5hmC 5-hydroxymethylcytosine 5mC 5-methylcytosine α-KG α-ketoglutarate βOHB D-β-hydroxybutyrate AC adenylylcyclase ACLY ATPcitratelyase ACSS2 acyl-CoAsynthetaseshortchainfamilymember2 AICDA activation-inducedcytidinedeaminase Air antisenseinsulin-likegrowthfactor2receptorRNA AML acutemyeloidleukemia AMPK AMP-activatedproteinkinase ARID AT-richinteractiondomain ASIP Agoutisignalingprotein ATRX α-thalassemia/mentalretardationsyndromeX-linked BAF BRG1-associatedfactor BDNF brain-derivedneurotrophicfactor BER baseexcisionrepair BET bromodomainandextra-terminal BMI bodymassindex BMI1 BMI1proto-oncogene,Polycombringfinger BMP bonemorphogeneticprotein bp basepair CAGE capanalysisofgeneexpression CaMKII calcium/calmodulin-dependentkinaseII CBFB core-bindingfactorsubunit-β CDKN cyclin-dependentkinaseinhibitor CEBP CCAAT/enhancerbindingprotein ix x ListofAbbreviations CFP1 CXXCfingerprotein1 ChIP chromatinimmunoprecipitation CIMP CpGislandmethylatorphenotype CK1 caseinkinase1 CLL chroniclymphoidleukemia CLP commonlymphoidprogenitor CML chronicmyeloidleukemia CMP commonmyeloidprogenitor CREBBP CREBbindingprotein,alsocalledKAT3A CTCF CCCTCbindingfactor DBD DNA-bindingdomain DMR differentiallymethylatedregion DNMT DNAmethyltransferase DOHaD developmentaloriginsofhealthanddisease EMT epithelial-to-mesenchymaltransition ENCODE encyclopediaofDNAelements EP300 E1Abindingproteinp300,alsocalledKAT3B EPHA4 EPHReceptorA4 ERK extracellularregulatedkinase eRNA enhancerRNA ES embryonicstem EWAS epigenome-wideassociationstudy EZH enhancerofzestehomolog FAD flavinadeninedinucleotide FAIRE formaldehyde-assistedisolationofregulatoryelements FANTOM FunctionalANnotaTionOftheMammaliangenome FDA FoodandDrugAdministration FISH fluorescenceinsituhybridization FMR1 fragileXmentalretardation1 FOX forkheadbox FXN frataxin GATA GATAbindingprotein GMP granulocyte-monocyteprogenitor GPCR Gprotein-coupledreceptor gRNA guideRNA GTEx GenotypeTissueExpression GWAS genome-wideassociationstudy HAT histoneacetyltransferase HDAC histonedeacetylase HGPS Hutchinson-Gilfordprogeriasyndrome HMG high-mobilitygroupprotein HNRNPU heterogeneousnuclearribonucleoproteinU HOTAIR HOXtranscriptantisenseRNA HOTTIP HOXAtranscriptatthedistaltip HP1 heterochromatinprotein1 ListofAbbreviations xi HSC hematopoieticstemcell HTT Huntingtin IAP intracisternalAparticle ICM innercellmass ICR imprintcontrolregion IDH isocitratedehydrogenase IGF2 insulin-likegrowthfactor2 IHEC InternationalHumanEpigenomeConsortium IHH Indianhedgehog IL interleukin INFG interferonγ INO80 INO80complexsubunit iPS inducedpluripotentstem ISWI imitationSWI IVF invitrofertilization KAT lysineacetyltransferase kb kilobasepairs(1,000bp) KCNQ1 potassiumvoltage-gatedchannelsubfamilyQmember1 KDAC lysinedeacetylase KDM lysinedemethylase KLF4 Krüppel-likefactor4 KMT lysinemethyltransferase LAD lamin-associateddomain LCR locuscontrolregion LDH lactatedehydrogenase LINE longinterspersedelement LOCK largeorganizedchromatinK9-modification LPS lipopolysaccharide LSD1 lysinespecificdemethylase1,alsocalledKDM1A LTP long-termpotentiation MAGEA1 melanoma-associatedantigen1 MALAT1 metastasisassociatedlungadenocarcinomatranscript1 MAPK mitogen-activatedproteinkinases MAT2A methionineadenosyltransferase2A MBD methyl-DNAbindingdomain mCH non-CpGmethylation MCPH1 microcephalin MECOM MDS1andEVI1complexlocus MeCP2 methyl-CpGbindingprotein2 MEK mitogen-activatedproteinkinasekinase MEP megakaryocyte-erythrocyteprogenitor MHC majorhistocompatibilitycomplex MICA MHCclassIpolypeptide-relatedsequenceA miRNA microRNA MLL mixedlineageleukemia
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