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Levelsofgeneexpressioncontrolineukaryotes
Transcription
Precursor‐RNAprocessing
mRNAtransport
Translation
RNAdegradation
Proteindegradation
RNAProcessingControl
Regulatestheproductionofmature‐RNAfrom
precursor‐RNA:
1.Choiceofalternativepoly(A)site
toproducedifferentpre‐mRNAmolecules
2.Choiceofalternativesplicingsite
toproducedifferentfunctionalmRNAs
RNATransportControl
spliceosomeretentionmodel
?
Spliceosome(thesplicingcomplexesformedbythe
associationofseveralsnRNPsboundtothepre‐mRNA)
assemblycompeteswithnuclearexport
?
Aftersplicingprocess,intronisassociatedwithsnRNPs
beforedegradation
?
The
methylated5’capisnecessaryformRNAtobe
exportedtothecytoplasm
TranslationalTimingControl
maskedmRNAs
Deadenylation:inthe3’UTRofmRNA,upstreamof
AAUAAAsequence,thereisaconsensussequence
(AU)‐richelement(ARE)as
(UUUUUAU).
deadenylationsignal
Polyadenylation:toactivateastoredmRNAinthis
class,thissignal(AREelement)isrecognizedbya
polyadenylationenzymeandadd~150As
Samesignalfordeadenylationandpolyadenylationincytoplasm
RNAdegradationcontrol
?
Deadenylation‐dependentdecaypathway
–
poly(A)tailaredeadenylateduntilthetailaretooshort(5‐15As)
tobindPAB(polyAbindingprotein)
Then5’capisremoved(decaping)(DCP1)
5’‐to‐3’exonucleasedegradationAllareenzyme‐catalyzedprocesses
–
–
?
Deadenylation‐independentdecaypathway
–
–
–
Yeastdcp1mutantiscapabletodegrademRNA
Decapingwithoutbeingdeadenylated
Rapiddegradationby5’‐to‐3’exonuclease,orbecleaved
internallyw/obeingdeadenylated,andthenbrokendownfurther
Proteindegradationcontrol
E1:ubiquitin-activatingenzyme
E2:ubiquitin-conjugatingenzyme
E3:ubiquitin-proteinligases
AproteintaggedfordestructionoftenrequiresseveralmoleculesofUbiquitin.
GeneRegulationinDevelopment
andDifferentiation
‐‐‐‐long‐termgeneregulation
DevelopmentandDifferentiation
Keypoints
Whataredevelopmentanddifferentiation?
Doesthegenomeremainconstantduring
development,oristherealossofDNA?
Exampleofdifferentialgeneactivityduring
development‐hemoglobin
Howdogenerearrangementsgenerateantibodydiversity?
DevelopmentandDifferentiation
Complexeukaryoteshavemanydifferentcells,
tissuesandorganswithspecializedfunctions,
yetallcellsofthesameorganismhavethe
samegenotype
Duringanorganism’sdevelopment,cellsthat
aregeneticallyidenticalbecomephysiologicalandphenotypicallydifferentiatedintermsoftheirstructureandfunction
DevelopmentandDifferentiation
Developmentistheprocessofregulated
growththatresultsfromthegenome’s
interactionwithcytoplasmandthecellularexternalenvironmentandinvolvesaprogrammedsequenceofcellular‐level
phenotypiceventsthataretypicallyirreversible
Thetotalofthephenotypicchangesconstitutes
thelifecycleofanorganism
DevelopmentandDifferentiation
Developmentalpotential‐describestherange
ofdifferentcelltypesitCANbecome.
Totipotencyiscommoninplants,butis
uncommoninanimalsafterthe2‐4cellstage.
Asdevelopmentprogresses,thedevelopmental
potentialofmostindividualcellsdecreasesuntil
theirfateisdetermined.
DevelopmentandDifferentiation
Thedeterminationofdifferentcelltypes(cell
fates)involvesprogressiverestrictionsintheir
developmentalpotentials.
Whenacell“chooses”aparticularfate,itis
saidtobedetermined,althoughitstill"looks"
justlikeitsundeterminedneighbors.
Determinationimpliesastablechange‐the
fateofdeterminedcellsdoesnotchange.
Mechanismsofcellulardetermination
Insomecases,determinationresultsfromtheasymmetricsegregationofcellulardeterminants.
Mechanismsofcellulardetermination
However,inmostcases,determinationistheresultofinductivesignalingbetweencells.
DevelopmentandDifferentiation
Differentiation,themostspectacularaspect
ofdevelopment,involvestheformationof
differenttypesofcells,tissuesandorgansthroughtheprocessesofspecificregulationofgeneexpression
Differentiatedcellshavethecharacteristic
structuralandfunctionalproperties
DevelopmentandDifferentiation
Differentiationresultsfromdifferentialgeneexpression:ahighlyprogrammedpatternofgeneactivationandgenerepression
HowMuchDNA
CodesforProtein
Eukaryoticgenomes
Unique‐sequenceDNA–onetoafewcopies
RepetitiveDNA–manycopies
ModeratelyrepetitiveDNA–afewto105copies
HighlyrepetitiveDNA–105to107copies
DispersedrepeatedDNA(InterspersedrepeatedDNA)
Shortinterspersedrepeatedsequence(SINEs):100‐500bp
Longinterspersedrepeatedsequence(LINEs):≥5000bp
TandemlyrepeatedDNA
Shorttandemrepeat(STR,microsatellite):2‐4bp
Variablenumberoftandemrepeats(VNTR,minisatellite):5‐10bp
HUMANGENOME
GenomicActivityinMulticellularEukaryotes
?
20to40percentofthegenomicDNAishighly
repetitiveDNA(doesnotencodeprotein)
Theremaining60to80percentoftheDNAisdistributedbetweenmoderatelyrepetitiveand
?
unique-sequence
DNA
?
Atanyonetimeamaximumofabout6%of
theuniquesequenceDNAistranscriptionallyactiveandproducingprotein(seaurchin)
ConstancyofDNAintheGenomeDuringDevelopment
Regenerationofcarrotplantsfrommaturesinglecells
Cloning
animals
Differentialgeneactivityamongtissuesandduringdevelopment
Hemoglobintypesandhumandevelopment
Immunogeneticsandchromosomerearrangementsduringdevelopment
AssemblyofantibodygenesfromgenesegmentsduringBcelldevelopment
ConstancyofDNAintheGenomic
DuringDevelopment
?
Whetherdevelopmentanddifferentiation
involvealossofgeneticinformation(i.e.,ofDNA),orwhethertheseprocessesinvolveaprogrammedsequenceofgeneactivationandrepressionwithaconstantgenome,thatis,agenomethatisthesameinalladultcellsasitisinthezygote?
RegenerationofCarrotPlantsfrom
MatureSingleCells
?
?
?
?
1950s,FrederickSteward
DissociatephloemtissueofacarrotSeparatethecells
Culturenewcarrotplantsfromthosecellsusingplanttissueculturetechniques
Cloningofamaturecarrotplantfromacellofamaturecarrot
DNAcontentofacellremainsconstantduringdevelopmentanddifferentiation
CloningAnimals
?
Annucleusfromaskincellofanadultfroginjected
intoanenucleatedeggcoulddirectdevelopmenttothetadpolestage
Cloningofasleep,thenmice,cattleandmonkeyAdifferentiatedadultsomaticnucleushasallthe
geneticinformationnecessarytodirectdevelopment
againfromthestart
Thenucleusissaidtobetotipotentortodemonstratetotipotency
?
?
?
RepresentationofWilmot’ssheepcloningexperiment,whichshowedthetotalpotencyofthenucleusofadifferentiated,adultcell
?
步驟一:從一只6歲芬蘭多塞特白面母綿羊(A)的乳腺中取出乳腺細胞,將其放入低濃度的營養(yǎng)培養(yǎng)液中,細胞逐漸停止分裂,此細胞稱之為“供體細胞”;
步驟二:從一頭蘇格蘭黑面母綿羊(B)的卵巢中取出未受精的卵細胞,并立即將細胞核除去,留下一個無核的卵細胞,此細胞稱之為“受體細胞”;
步驟三:利用電脈沖方法,使供體細胞和受體細胞融合,最后形成“融合細胞”。從而形成“胚胎細胞”;
步驟四:將胚胎細胞轉移到另一只蘇格蘭黑面母綿羊(C)的子宮內,胚胎細胞進一步分化和發(fā)育,最后形成小綿羊--多莉。
?
?
?
Cloning101
Keynote
Thepreciseregulationofactivationandrepressionofspecificgenesisresponsiblefortheprocessofdevelopmentanddifferentiation.
DevelopmentanddifferentiationresultfromdifferentialgeneactivityofagenomethatcontainsaconstantamountofDNA,fromthezygotestagetothematureorganismstage.
ConstancyofDNAintheGenomeDuringDevelopment
Regenerationofcarrotplantsfrommaturesinglecells
Cloning
animals
Differentialgeneactivityamongtissuesandduringdevelopment
Hemoglobintypesandhumandevelopment
Immunogeneticsandchromosomerearrangementsduringdevelopment
AssemblyofantibodygenesfromgenesegmentsduringBcelldevelopment
DifferentialGeneActivityAmong
TissuesandDuringDevelopment
?
Specializedcelltypehavedifferentcell
morphology,forexample,nervecellsareclearlydifferentfromintestinalepithelialcells
?
SincetheamountofDNAtypicallyremains
constantduringdevelopment,thesimplesthypothesisisthatthephenotypicdifferencesbetweendifferentcelltypesreflectdifferentialgeneactivity
HemoglobinTypesandHumanDevelopment
?
HumanadulthemoglobinHb-Aisatetrameric
proteinmadeupoftwoαandβpolypeptides.Eachtypeofpolypeptideiscodedbyaseparategene,αglobinandβglobin.
Structureofhumanhemoglobin
Red--αsubunitsBlue–βsubunits
Green–ironcontaininghemegroups
PDBID:1GZX
Molecularorganizationofthehuman‐
globinand‐globingenes
HemoglobinTypesandHumanDevelopment
?
HemoglobinHb-Aisonlyonetypeof
hemoglobinfoundinhumans.
?
Thereareseveralgenescodeforαandβ-like
globinpolypeptides,whichformdifferenttypesofhemoglobinatdifferenttimesduringhumandevelopment
Comparisonofsynthesisofdifferentglobin
chainsatgivenstagesofdevelopment
Linkagemapsofhumanglobingeneclusters
Sicklecellanemia
Classicalsicklecellanemiaisadevastatingdiseasethatafflictsasmanyas1in64blacksinAfricaandfrom1in200to1in400blacksintheUnitedStates
SicklecellanemiaiscausedbyanAtoTtransversioninthesixthcodonofthehumanβ-globingene(GAGGTG)resultinginaglutamicacidtovalinesubstitutionintheprotein
Itcausedeoxygenatedhemoglobintoaggregate,resultinginalterationintheredbloodcellsshapeandblockbloodflow
Effortsaremadetoupregulateγ-globin(fetalformofhemoglobin)orδ-globin(preventionofβ-globinaggregation)toalleviatesdiseasesymptoms
SickleCellAnemia
SickleCellDisease
ConstancyofDNAintheGenomeDuringDevelopment
Regenerationofcarrotplantsfrommaturesinglecells
Cloning
animals
Differentialgeneactivityamongtissuesandduringdevelopment
Hemoglobintypesandhumandevelopment
Immunogeneticsandchromosomerearrangementsduringdevelopment
AssemblyofantibodygenesfromgenesegmentsduringBcelldevelopment
ImmunogeneticsandChromosome
RearrangementsDuringDevelopment
Thecellsresponsibleforimmunespecificityare
lymphocytes,specificallyTcellsandBcells.
Blymphocytesdevelopintheadultbonemarrow
Whenactivatedbyanantigen,Bcellsdevelopintoplasmacellsthatmakeantibodies,thatis,specializedproteinscalledimmunoglobulins(Igs)
Antibodymoleculesareinsertedintheplasmamembraneoftheplasmacells,andtheyarealsoreleasedintothebloodandlymph,wheretheyareresponsibleforthehumoralimmuneresponses.
?
?
?
?
ImmunogeneticsandChromosome
ReaarangementsDuringDevelopment
Forthehumoralresponsesystem,thereisapopulationofBcells,eachofwhichcanrecognizeasingleantigen.
AparticularBcellrecognizesanantigenbecausetheBcellhasmadeantibodymolecules,whichareattachedtotheoutermembraneofthecellandactasreceptormolecules.
Anygivencellmakesonlyonespecifickindofantibodytowardonespecificantigen.
ImmunogeneticsandChromosome
ReaarangementsDuringDevelopment
?
Inmammals,therearefivemajorclassesof
antibodies:IgA,IgD,IgE,IgGandIgM.
TheyhavedifferentHchains:α,δ,ε,γandμ,respectively
TwotypeofLchainsarefound:κandλ.BothLchaintypesarefoundinallIgclasses.
?
?
IgGantibodymolecule
AssemblyofAntibodyGenesfromGene
SegmentsDuringBCellDevelopment
?
?
Mammalmayproduce106to108differentantibodies
Theseantibodiestheoreticallywouldrequire103to104differentLchainsand103to104differentHchains
Theproblemisthatthehumangenomecontainonly~105gene
Howthediversityofantibodiesbegenerated?
?
?
?
VariabilityinLandHchainsresultsfromparticularDNArearrangementthatoccurduringBcelldevelopment
AssemblyofAntibodyGenesfromGene
SegmentsDuringBCellDevelopment
?
TheserearrangementsinvolvethejoiningofdifferentgenesegmentstoformagenethatistranscribedtoproduceanIgchain,theprocessiscalledsomaticrecombination
?
Thepermutationsofrecombinationareresponsiblelargelyforthediversityofantibodystructure.
Productionofkappa()lightchaingeneinmouse
L-leadersequence
J-joiningsegments
?
?
350Vk*4Jk=1400
FurtherdiversityresultsfromimprecisejoiningoftheVksegments
andJkgene
LightChainGene
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