Selected topics in Transcription Nir London. Computational Biology Seminar 2006.
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Selected topics in Transcription
Nir London.Computational Biology Seminar 2006
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Overview
• Elongation– Pause; Arrest– Chromatin remodeling; Histones– CTD
• Mediator Complex– Mechanism model– Composition and Interaction network
• Initiation Mechanism– New findings
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Elongation
• 17 BP Open bubble • 5’ to 3’ Elongation• 50-90 BP / second
Leninger 5’th edition
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Elongation reaction
• 3 ASPs highly conserved across all species
Leninger 5’th edition
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Elongation by RNA polymerase II: the short and long of it
Robert J. Sims, III, RimmaBelotserkovskaya and Danny Reinberg
Genes & Dev. 2004
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What’s stopping elongation?
• Efficient elongation must overcome several blocks.– Transcriptional pause– Transcriptional arrest– Transcriptional termination
• Many elongation factors serve to counteract or remove one of the above.
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Pause
• The RNA polymerase halts elongation for a time before resuming on its own.
• Pausing of bacterial RNA pol is caused by a structural rearrangement within the enzyme and DNA sequence.
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Easy modulation of rate?
• Demonstrated for all three eukaryotic RNA polymerases, viral and prokaryotic.
• Pausing is self-reversible a natural mode of transcriptional regulation.
• Many factors modulate transcriptional pause and thus, the rate of elongation.
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Pause to cap
• DSIF/NELF complex promotes pausing and enables capping
• TFIIF < Elongins < ELLs promote elongation at different places along the gene.
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Arrest
• Irreversible halt to synthesis. Pol cannot resume without additional factors
• The polymerase “backtracking” relative to the DNA template
• Misalignment of the catalytic site and 3-OH of the transcript
• Pause decays into arrest in a time dependent fashion
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Resume mechanism
• Resuming uses an evolutionarily conserved mechanism
• Requires cleavage of the RNA transcript in a 3’-to-5’ direction
• Cleavage allows the proper realignment of the active site and 3’-OH.
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TFIIS – Arrest solver
• The cleavage reaction is intrinsic to the Pol. Enhanced in the presence of TFIIS.
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TFIIS (cont.)
• An acidic hairpin coordinating a metal ion Re-aligns the RNA to the cleavage active site.
Kettenberger H. et al. 2003
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Nucleosomes – another block
• How does the Pol. Traverses the nucleosomes ?
• Models:– Nucleosome mobilization– Histone depletion
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Swi\Snf – ATP dependent chromatin remodeler
• Transcription pauses shortly after initiation.
• HSF1 alleviates the negative effect of chromatin structure.
• Recruits Swi\Snf to Hsp70 gene
• Both Activator and Swi\Snf are required for transcription on nucleosomal templates.
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Mechanism?
Narlikar GJ. Et al. Cell 2002
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FACT – histone chaperone
• Highly conserved
• ChIP showed it to be localized downstream to promoters of active genes upon induction
• Destabilize the nucleosome by removing one H2A/H2B dimer.
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Spt6
• Promotes nucleosome assembly in vitro
• Spt6 mutants show alterations in chromatin structure
• Colocalized to transcribed regions
• Interacts with H3
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Mechanism
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Histone Modifications and elongation
• Histone acetylation destabilizes chromatin structure
• No evidence for a specific role of histone acetylation in elongation
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Set1/2 - Methylation
• Methylation can co-map with silent or active regions – depend on Lys
• Linking CTD to histone modifications• Set2 - H3-K36-specific histone methyltransferase• Set2 associates with the hyperphosphorylated RNAPII• Deletion of the CTD, or the CTD-kinase Ctk1, results in a
loss of H3-K36 methylation• Set1 functions as a specific histone H3-K4
methyltransferase• Set1 interacts with the Ser-5 phosphorylated form of
RNAP II. the form associated with early transcriptional events
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Chd1
Iws1
Swi/Snf
Spt6 FACT
DSIF
TFIIS
P-TEFb
Paf
ISWII
Elongator
Set1
Set2
TFIIF
Spt2
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CTD
• CTD serves as a platform for many factors for mRNA maturation
• Different phosphorylation patterns creates different structures
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Flexible
• A) Cgt1-CTD
• B) Pin1-CTD
• Heptad repeats are not identical
• Could explain specific factor binding
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Conclusions?
• Why are there so many redundant EF’s ? – The answer might be that they are
promoter/gene specific
• How does elongation and chromatin remodeling work together ?
• How histone modifications translate to distinct functional outcomes ?
• Why is the rate of elongation in vitro, far less than the rates observed in vivo ?
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The yeast Mediator complex andits regulation
Stefan Bjorklund and Claes M. Gustafsson
TRENDS in Biochemical Sciences, May 2005
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Mediator
• Required for activator dependent stimulation of Pol2.
• Comprised of 25 subunits
• Can be found as free form or attached to Pol2.
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Mediator interaction with Pol2
• CTD reminder: – Initiation – unphosphorylated – Elongation – phosphorylated
• Mediator complex interacts directly with the unphosphorylated form of the CTD
• Dissociation upon elongation
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Transcriptional activation
• The model: Mediator acts as a bridge between activators and basal Pol2 machinery.
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Activator Example – GAL4
Transcription Transcription Transcription Transcription
• Gal4 interacts directly with subunits Med15, Med17.
• ChIP showed association to be at an upstream activation sequence.
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Separate recruitment
• 3 waves of TF recruitment:
• Separate recruitment has also been showed for other promoters.
• Demonstrated in higher eukaryotes• Mediator forms a scaffold for several rounds of
transcription
Galactose
0
SAGA
4-7
Mediator
6-10
Pol II
8-13
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Transcriptional repression
• Srb8-11 identified as crucial for mediated repression– Tup1 repressor recruits Srb8-11
containing mediator– Srb10 kinase function is necessary
for repression– Srb8-11 genes showed in genetic
screens loss of repression
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Transcriptional repression
• The model: repressors recruit mediator in a form in which interactions with Srb8-11 module are stabilized.
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Example – C/EBPβ
• Switch phosphorylated by Ras
• Active form recruits mediator devoid of Srb8-11
• Repressive form recruits Srb8-11 containing mediator
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Post translational modifications
• Irregularities in SDSpage migration for certain subunits.
• Treatment with phosphatase changed migration patterns
• ATP-analog experiments showed that Kin28 (part of TFIIH) phosphorylates not only the CTD but also the mediator
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Modifications (cont.)
• Other kinases target mediator: (Srb10, ras, PKA)
• Another option for signaling pathways to modulate transcription
• The effects of modifications aren’t characterized – Lots more to investigate
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Sub summary
• Mediator influences both recruitment of Pol. and initiation of transcription
• Might be involved in other transcription related processes (elongation, chromatin remodeling, splicing, RNA export)
• How does PT modifications affect mediator function ?
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A high resolution protein interaction map of
the yeast Mediator complex
Benjamin Guglielmi, Nynke L. van Berkum,
Benjamin Klapholz, Theo Bijma, Muriel
Boube, Claire Boschiero, Henri-Marc
Bourbon, Frank C. P. Holstege and Michel
Werner
Nucleic Acids Research, 2004.
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Pair-wise 2H analysis
• Each subunit was cloned as fusion protein with Gal4 DNA binding domain (GBD) or Gal4 Activation domain (GAD).
• Transformed into a GAL promoter-reporter genes strains.
• All possible matings were preformed.
Strains expressing GBD-Med2, Med3, Med4, Med13, Med15 showed strong expression of gal and were excluded from this analysis.
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Results
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Results (cont.)
• Identified interactions were retested by co-transformation to same strain
• 11 interactions found in middle-middle
• 7 interactions in head-head
• No interactions in tail
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Screening genomic lib.
• Some interactions can’t be discovered using complete proteins
• Same screen only now attached to GAD are random S. cerevisiae genomic seqs.
• 17 interactions were found. (7 new ones)
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Med31 – new subunit
• Med31 homologues found in mediator like complexes in higher eukaryots
• Fusion with GBD against all other 24 showed 2 interactions in middle section
• CoIP with Med17 confirmed it belongs to the mediator complex
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"בואו נחבוש את כובע הביקורת..."
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Interaction Domains
Truncation of conserved areas reveals different interaction domains for Med subunits.
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Abortive Initiation and ProductiveInitiation by RNA Polymerase
Involve DNA ScrunchingAndrey Revyakin, Chenyu Liu, Richard H.
Ebright, Terence R. Strick
Science Nov. 2006
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Initiation
• Transcription initiation is composed of:– RNAP binds to promoter (closed complex)– Unwinds 1 turn of DNA (open complex)– Abortive cycles of synthesis and release of
short RNA products (promoter initial transcribing complex)
– Upon synthesis of ~9-11 RNA nt enters into elongation (promoter escape)
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Abortive initiation mystery
• Two contradicting observations:– RNA products of 8-10 nt are synthesized –
Thus the active center translocates relative to the DNA.
– Footprinting results indicates that the upstream DNA protected by RNAP is the same in RPo and RPitc – thus RNAP appears not to translocate relative to DNA.
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Three models
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Unwinding detection
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Proving the scrunch
• The scrunching model is the only model that requires RNAP dependent DNA unwinding
• For each BP the RNAP pulls into itself, there another BP of DNA unwinding
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Scrunching in abortive init.
• If no NTP are added we receive RPo
• If only some NTP’s are added we receive RPitc<8
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Does scrunching requires RNA?
• Control I : only initiating A -> RPitc<=1
• Control II : rifampicin -> RPitc<=2
• Scrunching doesn’t occur -> requires an RNA product > 2 nt in length
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RNA length and scrunching
• Tested on: – RPo (no NTP’s)– RPitc<4 (only A, U)– RPitc<8 (only A, U, C)
• Transition from 0 to 4 shows 2 bp unwinding
• Transitions from 0 to 8 shows 6 bp unwinding
• Simplest model : N-2
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Productive initiation
• Constructs: Promotor-[400/100 bp]-Terminator.• Four transitions observed:
– Transition from initial state to RPo– Transition to scrunched RPitc– Transition to a “elongation state” – Transition to initial state again
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Controls
• No NTP’s RPo transition 1• A,U,C RPitc<8 transition 1,2• All NTP’s, halted elongation transition
1,2,3• All NTP’s, no terminator transitions
1,2,3• Length of transcribed region varied
duration of phase between 3 and 4 changed
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Conclusions
• Promoter escape requires RNA product ~9 to 11 nt in length.
• Thus requires scrunching of ~7 to 9 bp (N – 2), • Assuming an energetic cost of ~2 kcal/mol per
bp, a total of ~14 to 18 kcal/mol is accumulated in the stressed intermediate.
• RNAP-promoter interaction are ~7 to 9 kcal/mol• RNAP-initiation-factor interaction ~13 kcal/mol
(s70)
The energy accumulated in thatobligatory stressed intermediate drives the transition from initiation to elongation.
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PAF – elongation complex
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Gal11 module
• 3D EM reconstruction shows two conformations.
• Tail region doesn’t interact with Pol2
• Gal11 (Med[2,3,15,16]) module might function as a separate entity
• Associates with Gcn4 and promotes transcription of ARG1, SNZ1 genes
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Gal11 (cont.)
• Option 1: interacts with SAGA or SWI/SNF complexes, which is enough for initiation complex
• Option 2: direct stimulatory effect on transcription machinery