Nucleosomes: what, why and where?rpdata.caltech.edu/.../lectures/NucleosomeClass3.pdf ·...
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Nucleosomes:what,whyandwhere?
RobBrewster
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OutlineWhatisanucleosome?
‐howisDNApackaged/organizedinEukaryotes?
Whydonucleosomesform?
‐DNAissEff,howdo~100bploopsformsoreadily?
Wheredonucleosomesform?
‐ Whatcontrolsthespacingandstructureofnucleosomesonthechromosome?
AccessibilityofDNAinthenucleosomes
‐HowisDNAinsideanucleosomesaccessed?
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DNAOrganizaEoninEukaryotesDNAispackagedandcondensedintochromosome
‐ Humangenomeisbig,nucleusissmall~2billionbasepairs≈2mnucleusradius~6µm
‐ ManydifferentlevelsoforganizaEon‐ Compactschromosome‐ RegulatestranscripEonbymakingporEonsofthechromosomemore/lessaccessible(upto80%isinaccessibletoproteinbinding)
‐ WewillfocusonnucleosomeformaEon
(Alberts,EssenEalCellBiology1998)
(LeeWetal.,Nat.GeneEcs2007)
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ElectronmicrographofchromaEnatlowionicstrength
‐Nucleosomesappearas“beadsonastring
BasicrepeaEngstructurecanbeprobed(protectandseqmethod)
‐DigesEonenzymecutsaccessibleregionsofDNA
‐DNAprotectedbynucleosomeisnotcut
Whatisanucleosome?
(FuruyamaandBiggins,PNAS)
(ElectronMicrographfromOlinsandOlins)
Mono Dual Mono Mono
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EnzymaEcdigestsParEcularenzymescancutdoublestrandedDNAbetweenbasepairs
‐MosthavespecificrecogniEonsites
‐Micrococcalnucleasecleaveseverythingitcan(nospecificseq.)DiluEonofnuclease1:3
(picturesfromNEB)
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(PeterJ.Russell,iGene%cs)
RepeaEngstructurecontains5differentproteins
‐Mainbodyisanoctomerformedfrom:twocopieseachofH2A,H2B,H3,H4
‐DNAwraps147bp(1.75turns)aroundthecore
‐14nonspecificadhesivecontactswith histone(majorgroove–histone)
‐H1agachestothelinkerregionandchangestheconformaEon;requiredforchromaEnformaEon
‐H1covers30‐50bp
Structureofindividualnucleosome
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DNArigidityDNAissEff…
‐~150bppersistencelength,λ,forlysedbacterialgenome
‐loopssmallerthanλshouldberare
…butnotthatsEff‐singleturnaroundhistonecore~100bp
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BackofthepowerpointcalculaEonEnergypaidtobendloopof147bpDNAin16.5bpcircle
Assumeλ=150bpthen:
Thiscostmustbebalancedout(andthensome)bythe14contactssoeachcontactmustcontribute~3KT
However,nucleosomecontactsare~1.5KT(PolachandWidom,2005;Schiessel,2003)
ReversingthisandsolvingformaximumsEffnessforstablenucleosomes,λ<~80bp
Whatgives?
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(ClouEerandWidom,MolecularCell2004)
Loopingprobabilityforsmallfragmentsislargerthanexpected
‐~100bpfragmentsformloopsmorereadilythanpredicted
‐certainsequencesaremoreflexiblethanothers
‐sequenceswhichloopmorereadilyalsomorereadilyformnucleosomes(asmuchas10^3‐folddifference)
DoesthissequencedependencecontrolwherenucleosomesareposiEoned?
BendingofshortDNAfragments
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TheEukaryoEcgenome!‐FormaEononYeastgenomeismoreprobablethanfore.coligenome
‐ImpliesEuk.GenomehassequencepreferenEalfornucleosomes
EukaryoEcgenomeshowsspecificpagerns‐AA/AT/TTdinucleoEdefrequency~10bp(oneDNAtwist)
WhereareNucleosomes?
(Zhangetal.,Naturestruct.&mol.bio.,2009)
PowerSpectrumofAA/AT/TTrepeats
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Nucleosomecode
10bpPeriodicityisevidentbothinvivoandinvitro‐GCis5bpoutofphasewithATdinucleoEdes
‐duetobendingdifferencesinGCandAT?
(Kaplanetal,nature2009)
Majorgroove
MajorgrooveWrap5bp
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Moreexamples
(Segaletal.,Nature,2006)
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Nucleosomevsrandomsequence
Periodicityismissingfromarbitrarysequences
(Segaletal.,Nature,2006)
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Method:Frominvivooccupancydata,calculatetheprobabilityofanydinucleoEdepairatagivennuc.posiEon.
Probabilitythat147bpsequenceSiswrapped:
ThestaEsEcalweightofalongersequencewithmulEplenucleosomesisjusttheproductoftheprobabilityforeverybasepairtobeinthatstate,
TheprobabilitymustnowbecomputedcomputaEonallyduetotheenormousnumberofpossibleconfiguraEons(C)
(Segaletal.,Nature,2006)
ProbabilisEcmodelofnucleosomeoccupancy
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ProbabilisEclandscapeforoccupancy
AtaparEcularnucleosomalcoveragecanpredictwherestablenucleosomeswillbelocated
(Kaplanetal,nature2009)
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PredicEonsfromthermodynamicmodel
Prob.ofcoveragebynuc
Predictedstablenuc
Exp.Determinednuc
Successratewithin32bpofpredictedposiEon
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StaEsEcalPosiEoning–A(semi)compeEngview
(Zhangetal.,Naturestruct.&mol.bio.,2009)
Variou
sTranscribe
dGen
es
Nucleosomespagernemergesfromstericexclusiononaline‐Promoterregionisalways“nucleosomefree”‐DNAsequenceappearstoplayonlyasmallrole
Less
more
InVitro
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Barrier HardSpheres
Random1Dhardspheregas?Occurrence
DistancefromTSS
PhasinginvivoresemblesRDFof(forinstance)LJGas
(Zhangetal.,Naturestruct.&mol.bio.,2009)
Canasimplemodelofa1DhardspheregaspredictnucleosomeposiEoningpagern?
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ConclusionsonposiEoning
DNAsequencemagersfornucleosomesposiEons…
‐preferenEallybindtoparEcularlyrepeaEngsequences
‐avoidlongtracksofA/T
…however,thiseffectseemstobeminimizedinvivo
‐Simple1DgasmodelfitsinvivonucleosomeposiEonswell (datanotshown)
Howdoesoneresolvetheapparentconflictintheseviews?
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AccessingnucleosomalDNAHowisprotectedDNAaccessed?
‐DNAreplicaEon,repairandtranscripEonallrequireaccesstooccludedDNA
‐Specializedmotorscalled“remodelingfactors”disassembleandperturbnucleosomestoallowaccess
‐However,evenwithoutthesemotors,wrappedDNAhassomeaccessibility
‐DigesEonassaysprobeequilibriumaccessibility
‐Fretprobesdynamicaccessibility
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Invitroaccessibilitymechanism
Whatisthemechanismtoaccessasiteburieddeepinthenucleosome?
TranslaEonalongdna
?? ?
Transientunwrapping
Bulgedstructures
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Invitroaccessibilitymechanism
Whatisthemechanismtoaccessasiteburieddeepinthenucleosome?
TranslaEonalongdna
? ?
Transientunwrapping
Bulgedstructures
Invitroaccessibilitydoesnotshowlengthdependencebeyond~100bp (Andersonetal,2002)
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FretonnucleosomalcomplexOnefretdyeisputonthenucleosome,oneisputontheendoftheDNAstrand
Exciteatlowwavelengths:
Dyesareclose–signal~680nmishigh
Dyesarefar–signal~680nmislow
(LiandWidom,2004)
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Invitroaccessibilitymechanism
Whatisthemechanismtoaccessasiteburieddeepinthenucleosome?
TranslaEonalongdna
!
Transientunwrapping
Bulgedstructures
Invitroaccessabilitydoesnotshowlengthdependencebeyond~100bp
FRETexperimentsbyLiandWidom
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Probingaccessibility
SpecificrestricEonenzymebindingsite
DNAiscleavedwhensitebecomesaccessiblefromunwrapping
MeasureprobabilityforbeingcutasafuncEonofburialdepth
Accessibilityisreduced(comparedtonakeddna)sitesburiedshallow10‐100x,deep~105x
(PolachandWidom,2000)
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Measuringunwrapping
Themoreflexiblesequenceislessaccessible!
WhereΔGisthechangeinfreeenergyassociatedwithopeningthebindingsite
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TheoryInterlude
NucleosomepreferenceisenErelybending?!
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γ=‐0.24kT/bp
Moreflexiblesequence(601TA)Morerigidsequence(5S)
γ=‐0.16kT/bp
Fizngbendingenergy
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b
WithR=13.5bp,a=10.5bp,L=147bp
However,forClouEerandWidomdata
bp
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RNAPtranscripEonthroughthenucleosome
(Hodgesetal,2009)
BeadagachedtoendofDNAandRNAP
‐RNAPmovementthroughthenucleosomecanbemeasured
‐DistancebetweenbeadsisareadoutforRNAPdepthinnucleosome
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ModelforRNAPtranscripEonthroughnucleosome
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Conclusions
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TheEnd
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DNAorganizaEon
E.Coligenome~4millionbp≈1.2mmE.Colidimensions~2µm^3
Humangenome~6billionbp≈2000mmNucleusdimensions~750µm^3
(Maghews,DNA Structure Prerequisite Informa%on.1997)
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Sequencepreferenceofnucleosomes
Nucleosomecode‐AA/TT/TAdinucleoEderepeats appearwith10bpperiodicity
‐GCrepeats5bpoutofphase
DuetodifferenceinbendingofdinucleoEdes?
‐HelicityofDNAmeansbendingatmajorandminorgrooveis opposite
‐NucleosomesmayposiEonAA/TA/TTatminor/major,GCatmajor/minorgrooveduetodifferenceinbending
(Segaletal.,Nature,2006)
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WhatisaNucleosome(howdoweknow)?DigesEonwith
‐ Humangenomeisbig,nucleusissmall~2billionbasepairs≈2mnucleusradius~6µm
‐ ManydifferentlevelsoforganizaEon
‐ WeareinteresEnginNucleosomeformaEon
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DNAorganizaEoninEukaryotes
OlinsandOlins
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DNAorganizaEoninEukaryotes
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Topics:‐GeneralintroducEontoNucleosomes ‐compacEoncomputaEon?‐ProtectandSeq:Widomhgp://www.wisdom.weizmann.ac.il/~eran/NucleosomeModel.pdf
weissmanhgp://www.nature.com/nmeth/journal/v6/n4/full/nmeth0409‐244b.html
‐Lacrastuff,pullingexp‐WidomAccessibility