Table Of ContentHuman 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
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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
