32 gene regulation in eukaryotes. lecture outline 11/28/05 gene regulation in eukaryotes...
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32 Gene regulation in Eukaryotes
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Lecture Outline 11/28/05• Gene regulation in eukaryotes
– Chromatin remodeling– More kinds of control elements
• Promoters, Enhancers, and Silencers• Combinatorial control• Cell-specific transcription
– Post transcription gene regulation• mRNA processing• Micro RNAs• Protein degradation
– Differentiation and Development • A cascade of transcription regulators• Examples from flowers and fruit flies
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Gene Regulation in Prokaryotes and Eukarykotes
• Prokaryotes– Operons
• 27% of E. coli genes• (Housekeeping genes
not in operons)
– simultaneous transcription and translation
• Eukaryotes– No operons, but they still
need to coordinate regulation
– More kinds of control elements
– RNA processing– Chromatin remodeling
• Histones must be modified to loosen DNA
– Short- and long-term regulation
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Figure 19.3
Signal
NUCLEUS
Chromatin modification:
Gene
DNA
RNATranscription
RNA processing
Transport to cytoplasmCYTOPLASM
Degradationof mRNA
Translation
Polypetide CleavageChemical modificationTransport to cellular destination
Active protein
Degradation of protein
Degraded protein
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Nucleosome
30 nm
(b) 30-nm fiber
DNA Packing
Protein scaffold
300 nm
(c) Looped domains (300-nm fiber)
Loops
Scaffold
700 nm
1,400 nm
Figure 19.2
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Histone Modification
Figure 19.4a
Chromatin changes
Transcription
RNA processing
mRNA degradation
Translation
Protein processingand degradation
DNAdouble helix Amino acids
availablefor chemicalmodification
Histonetails
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Histone acetylation loosens DNA to allow transcription
Figure 19.4 b
Unacetylated histones Acetylated histones
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Activator recruits chromatin remodeling and acetylation proteins
http://cats.med.uvm.edu
Densely packed chromatin
Transcription
RNA Pol
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Review transcription in Eukarkyotes
Enhancer(distal control elements)
Proximalcontrol elements
DNA
UpstreamPromoter
Exon Intron Exon Intron
Poly-A signalsequence
Exon
Terminationregion
Transcription
Downstream
Poly-Asignal
ExonIntronExonIntronExonPrimary RNAtranscript(pre-mRNA)
5
Intron RNA
RNA processing:Cap and tail added;introns excised andexons spliced together
Coding segment
P P PGmRNA
5 Cap 5 UTR(untranslated
region)
Startcodon
Stopcodon
3 UTR(untranslatedregion)
Poly-Atail
Chromatin changes
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Cleared 3 endof primarytransport
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Many components must be assembled to initiate transcription
Those common components are called “General Transcription Factors”
There are also many other transcription factors that control transcription of particular genes in particular conditions
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Control of Galactose metabolism in yeast
Two Repressor proteins bind to control region
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Control of Galactose metabolism in yeast
Galactose can bind to repressor complex. Opens activation site to stimulate transcription
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Distal controlelement
Activators
Enhancer
PromoterGene
TATAbox General
transcriptionfactors
DNA-bendingprotein
Group ofMediator proteins
RNAPolymerase II
RNAPolymerase II
RNA synthesisTranscriptionInitiation complex
Chromatin changes
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
A DNA-bending proteinbrings the bound activators
closer to the promoter.
2
Activator proteins bindto distal control elements.
1
The activators bind tocertain general transcription
factors and mediatorproteins.
3
Enhancers and activators
Fig 19.5
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Transcriptional synergy
• Combinations of different enhancers affect the strength of transcription
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How eukaryotic gene repressors can function:
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Cell type–specific transcriptionEnhancer Promoter
Controlelements
Albumin gene
Crystallin gene
Liver cellnucleus
Lens cellnucleus
Albumin geneexpressed
Albumin gene not expressed
Crystallin genenot expressed
Crystallin geneexpressed
Liver cell Lens cell
Fig 19.7
All cells have the same genes, but only certain genes are expressed in each tissue
Different set of activator proteins in the two cell types
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Long-term control of transcription: methylation
• Certain cytosine bases can be methylated, which blocks transcription– Usually CG dinucleotides– Recruits proteins which deacetylate
histones, inactivating nearby genes
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Genomic imprinting: inactivation of maternal or paternal genes
Some alleles are tagged by methyl C.
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Signal
NUCLEUS
Chromatin modification:
Gene
DNA
RNATranscription
RNA processing
Transport to cytoplasmCYTOPLASM
Degradationof mRNA
Translation
Polypetide
Active protein
Degradation of protein
Degraded protein
Post-transcription control of gene expression
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Alternative RNA splicingChromatin changes
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Exons
DNA
PrimaryRNAtranscript
mRNA
RNA splicing or
Fig 19.8
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Micro-RNAs
Chromatin changes
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Degradation of mRNAOR
Blockage of translation
Target mRNAmiRNA
Proteincomplex
Dicer
Hydrogenbond
The micro-RNA (miRNA)precursor foldsback on itself
1 Dicer cuts dsRNA into short segments
2 One strand of miRNA associates with protein.
3 The boundmiRNA can base-pair with any complementarymRNA
4Prevents geneexpresion
5
Fig 19.9
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Degradation of a protein by a proteasome
Chromatin changes
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Ubiquitin
Protein tobe degraded
Ubiquinatedprotein
Proteasome
Proteasomeand ubiquitinto be recycled
Proteinfragments(peptides)
Ubiquitin molecules are attached to a protein
1 The ubiquitin-tagged protein is recognized by a proteasome.
2The proteasome cuts the protein into small peptides.
3
Protein entering aproteasome
Fig 19.10
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Figure 21.1
Mutant Drosophila with an extra small eye on its
antenna
Development
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DNA
OFF OFF
OFFmRNA
mRNA mRNA mRNA mRNA
Anothertranscriptionfactor
MyoDMuscle cell(fully differentiated)
MyoD protein(transcription factor)
Myoblast (determined)
Embryonicprecursor cell
Myosin, othermuscle proteins,and cell-cycleblocking proteins
Other muscle-specific genesmyoDNucleus
Determination. Signals from other cells activate a masterregulatory gene, myoD,
1
Differentiation. MyoD protein activatesother muscle-specific transcription factors, which in turn activate genes for muscle proteins.
2
Determination and differentiation of muscle cells
Fig 21.10
The cell is now ireversibly determined
The cell is now fully differentiated
myoD is a “master control” gene: it makes a transcription factor that can activate other muscle specific genes.
The embryonic precursor cell is still undifferentiated
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DNA
OFF OFF
OFFmRNA
mRNA mRNA mRNA mRNA
Anothertranscriptionfactor
MyoDMuscle cell(fully differentiated)
MyoD protein(transcription factor)
Myoblast (determined)
Embryonicprecursor cell
Myosin, othermuscle proteins,and cell-cycleblocking proteins
Other muscle-specific genesMaster control gene myoDNucleus
Determination. Signals from other cells activate a master regulatory gene, myoD,
1
Differentiation. MyoD protein activatesother muscle-specific transcription factors, which in turn activate genes for muscle proteins.
2
Determination and differentiation of muscle cells
Fig 21.10The cell is now fully differentiated
The cell is now ireversibly determined to become a muscle cell.
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DNA
OFF OFF
OFFmRNA
mRNA mRNA mRNA mRNA
Anothertranscriptionfactor
MyoDMuscle cell(fully differentiated)
MyoD protein(transcription factor)
Myoblast (determined)
Embryonicprecursor cell
Myosin, othermuscle proteins,and cell-cycleblocking proteins
Other muscle-specific genesMaster control gene myoDNucleus
Determination. Signals from other cells activate a masterregulatory gene, myoD,
1
Differentiation. MyoD protein activatesother muscle-specific transcription factors, which in turn activate genes for muscle proteins.
2
Determination and differentiation of muscle cells
Fig 21.10
The cell is now ireversibly determined
The cell is now fully differentiated
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Genetic control of Flower Development
ApetalaClass A
AgamousClass C
PistillataClass B
“ABC Model”
These genes all code for transcription factors
Normal Flower
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The effect of the bicoid gene, an egg-polarity gene in Drosophila
Tail
Head
Normal larva
Tail Tail
Mutant larva (bicoid)
A mutation in bicoid leads to tail structures at both ends (bottom larva).
T1 T2T3
A1 A2 A3 A4 A5 A6 A7A8
A8A7 A6 A7
A8
Figure 21.14
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Hierarchy of Gene Activity in Early Drosophila Development
Maternal effect genes (egg-polarity genes)
Gap genes
Pair-rule genes
Segment polarity genes
Homeotic genes of the embryo
Other genes of the embryo
Segmentation genesof the embryo
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Drosophila pattern formation
Translation of bicoid mRNAFertilization
Nurse cells Egg cell
bicoid mRNA
Developing egg cell
Bicoid mRNA in mature unfertilized egg
100 µm
Bicoid protein inearly embryo
Anterior end
(b) Gradients of bicoid mRNA and bicoid protein in normal egg and early embryo.
1
2
3
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Homeotic genes
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• Regulatory genes that control organ identity
• Conserved from flies to mammals
Homeotic genes