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Facts:

- Bacteria(4000genes)

90%genesareinvolvedwithgrowthandprolifera=on10%genesdifferen=a=on

havegenesorganizedinoperons

promotersaresmallandveryspecific

- Yeasts(4500genes)

90%ofgenesareinvolvedwithgrowthandprolifera=on

10%ofgenesdifferen=a=onhavegenesdispersed

promotersaremediumsizeandveryspecific

- Mul=cellular(25000genes)

20%genesinvolvedwithgrowthandprolifera=on

40%genesinvolveswithdevelopment

40%genesinvolvedwithspecializedfunc=ons

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+

Howisamul=cellularorganismconstructed?

Highlyspecializedcells

zygote

To=potentcell

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Docellsloosegenesastheyareundergoing

developmentanddifferen=a=on?

CloningsaysNO!!

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Expressionofdifferentgenesindifferentcellstypes

DNAmicro-arrays

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Differentproteinsareproducedindifferent

=ssuesatdifferent=mes

2D-SDSproteingelelectrophoresis

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Regula=onofgeneexpressioncanoccuratmanydifferentstages

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Threekeycomponentsintheregula=onofgeneexpression:

1.  Signals: hormones(estrogen,testosterone,progesterone) Growthfactors(NGF,CSF,Interferon,…)

environment(drugs,toxicsubstances,metals)

2.Levelofresponse

transcrip=on

mRNAprocessing

mRNAtransportandlocaliza=on

mRNAtransla=on

mRNAstability

Proteinac=vity

3.Mechanisms

Transac=va=ngproteins

Methyla=on

X-inac=va=on

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Transcrip=onisini=atedbyproteinsrecognizingthePromoterofagene

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Transcrip=onfactorsbindspecificregulatorycis-ac=ngsequencesand

promotetranscrip=on

mRNA+1

TATA

-5000pb

RNApolyII

mRNA

TATA

-5000pb

“OFF”

“low”

mRNA

TATA

-5000pb“ON”

EnhancerBasic

promoter Transcrip=onfactors

+1

+1

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Transcrip=onfactorsrecogniseshortDNAsequences

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FamiliesofDNA-bindingtranscrip=onfactors

-DNAbinding

proteins

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Differenttypesofregula=on

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Organiza=onofaeukaryo=cpromoter

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Organiza=onofaeukaryo=cgeneregulatoryregion

GeneTATA-5000pb

Enhancer5’ Enhancer3’

BasicPromoter

Basicpromoter

hasfixed:

-posi=on

-distance

-orienta=on

Enhancers

havevariable:

-distance

-posi=on

-orienta=on

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Ac=vityofenhancersatadistance

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Ac=vityofenhancersatadistance

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Sequenceofeventsduringac=va=onoftranscrip=on

Histoneacetyla=onàgenetranscrip=on

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Assemblyoftranscrip=onalcomplexesatthepromoter

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Possiblepost-transla=onalmodifica=onsoftranscrip=onfactors

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Differen=alexpressionoffetalandmaternalglobingenes

γGγA

ε

β

δ

LowOxigenpressure,highaffinity

HighOxigenpressue,loweraffinity

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Glucoccor=coidsdiffusetothenucleusandcouldworkatmanydifferentpromoters

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Alterna=vesplicing:howtogetmoreproteinsoutof

yourgenome

30,000humangenesprobablygivemorethan100,000differentproteins

21 3 4calcitonin 5CGRP 6

5’ 3’

21 3 4calcitonin

21 3 4calcitonin 5CGRP 6

21 3 4calcitonin

21 3 5CGRP 6

AAAA…

AAAA…

DNA

Nuclear

Transcripts

mRNAs

Proteins

Thyroid

Neurons

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Alterna=vepromotersandsplicinga-amylase

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Regula=ngstabilityofmRNA

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Promoterdele=onstudies

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Promoterdele=on

studieswithGFPin

Wholeanimals

Conec=ve=ssuegrowth

factor

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CellularStress

Response

Manygenesupregulated

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ControlofGALregula=oninyeast

-  Ac=vatorproteinGAL4

-  InhibitoryproteinGAL80

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Eukaryo=cpromotersareverycomplexandreceivemul=plesignals

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0

Complexityofeukaryo=cpromoters

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Nuclearmatrixassocia=onofpromoters

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GenomawidemappingSARs/MARs

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Natureofinsulators

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Theeffectofcytosinemethyla=onupongeneexpression

HeritablepaernsofexpressionmaintainedthoughDNAreplica=on

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Theeffectofcytosinemethyla=onupongeneexpression

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Housekeepinggenes

CpGrepe==veblocksusuallymarkgenescons=tu=velyexpressed

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DrosophilaDevelopmentalGene=cs

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Combinatorialgenecontrolduringdevelopment

b l l d d l

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Combinatorialgenecontrolduringdevelopment

Th i = l d

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Theepigene=clandscape

ConradWaddington(1905-1975)

Th i = l d

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Theepigene=clandscape

ConradWaddington(1905-1975)

Th i = l d

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Theepigene=clandscape

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Epigene=cgeneregula=on