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Title: Transcription regulation of complex loci


1
Transcription regulation of complex loci
  • David Arnosti
  • Dept. Biochemistry Molecular Biology
  • Michigan State University

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Pioneers of the 19th century
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Pioneers of the 21st century
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  • A biologists wish list
  • Parts list operational system description

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  • A biologists wish list
  • Parts list operational system description
  • Predict function of cis regulatory sequences

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  • A biologists wish list
  • Parts list operational system description
  • Predict function of cis regulatory sequences
  • Build picture of transcriptional regulatory
    networks

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  • A biologists wish list
  • Parts list operational system description
  • Predict function of cis regulatory sequences
  • Build picture of transcriptional regulatory
    networks
  • Understand dynamic properties of system effect
    of
  • changes/mutations on output

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Tuesday Transcriptional regulation of complex
loci Wednesday Transcriptional logic machines
for developmental patterning
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Study the Form or the shadows on the cave wall?
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Compact regulatory regions in yeast
db.yeastgenome.org/cgi-bin/gbrowse/yeast/
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Dispersed regulatory regions in animals
Merli et al. (1996) Genes Dev. 101260
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Three lenses
Biochemistry
general, quantitative
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A word about genetic information
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Protein Coding
M P Q Q
5
3
AUGCCCCAGCAG
  • Information content dictated by
  • 5-3 orientation
  • Position with respect to an AUG
  • Phase (reading frame)
  • Location distal to a transcriptional start site

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Regulatory
Regulatory regions are bound by transcription
factors
Complexity stems from information being
read out as nucleoprotein complexes of various
structure and function.
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Regulatory
  • Move gene to particular nuclear compartment

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Regulatory
  • Move gene to particular nuclear compartment
  • Modify the chromatin structure of the gene

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Regulatory
  • Move gene to particular nuclear compartment
  • Modify the chromatin structure of the gene

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Regulatory
  • Move gene to particular nuclear compartment
  • Modify the chromatin structure of the gene
  • Directly contact components of the basal
    machinery

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Regulatory
  • Move gene to particular nuclear compartment
  • Modify the chromatin structure of the gene
  • Directly contact components of the basal
    machinery
  • 4. Influence the binding of cofactors

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Outline 1. Definitions 2. eve - one
gene/multiple enhancers 3. Globin locus - one
enhancer/multiple genes 4. HOX genes - boundaries
memory modules 5. Enhancer-promoter trafficking
and boundary elements
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Promoter
Enhancer
Silencer
Boundary Element
Cis regulatory element
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Outline 1. Definitions 2. eve - one
gene/multiple enhancers 3. Globin locus - one
enhancer/multiple genes 4. HOX genes - boundaries
memory modules 5. Enhancer-promoter trafficking
and boundary elements
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Body segmentation is presaged by segmental gene
expression.
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7
6
3
4
5
2
1
figure from Steve Small, NYU
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eve expression pattern evolves from broad pattern
to stripes
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Generalized activation
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Positional specification is dictated by
transcriptional repressors
Refinement through repression
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Short-range repressors Long-range
repressors
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Short-range repressors Long-range
repressors
giant knirps Kruppel snail
lt100 bp
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Short-range repressors Long-range
repressors
giant knirps Kruppel snail
hairy Dorsal repression complexes
lt100 bp
gt1,000 bp
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hair
y
knirp
s
Short-range Long-range
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CtB
P
groucho
hair
y
knirp
s
Short-range Long-range
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Histone
Deacetylases
CtB
P
groucho
hair
y
knirp
s
Short-range Long-range
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Histone
Deacetylases
CtB
P
groucho
hair
y
knirp
s
Short-range Long-range
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Histone
Deacetylases
CtB
P
groucho
hair
y
knirp
s
Short-range Long-range
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Two Models for Enhancer Design
Enhanceosome - smart but high-strung IFN-ß
enhancer
Billboard - dumb but flexible developmentally
regulated enhancers
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  • Enhanceosome
  • - extensive cooperative interactions
  • constrained placement of binding sites
  • monolithic activation (repression) complex

Kulkarni and Arnosti, Development 130, 6569.
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  • Billboard (information display)
  • - cis element provides loose grouping
  • multiple subelements - apparent redundancy
  • - overall output - integration over time of
    enhancer sampling

Kulkarni and Arnosti, Development 130, 6569.
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D. Tautz, U. Cologne
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Enhanceosome
Senger et al., (2004) Mol. Cell 13, 19
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Billboard
Clustered, but not necessarily conserved
Emberly et al., (2003) BMC Bioinformatics 457
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Berman et al. (2002) PNAS 99, 757-762
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Berman et al. (2002) PNAS 99, 757-762
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System modeling
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Quantitative Measurements
Janssens et al. (2005) Dev Genes Evol 215374-81
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Reinitz gene circuit dynamic model for
calculating the changing concentrations of
transcriptional regulatory proteins in the
embryo - involving 348 ordinary differential
equations for the matrix of nuclei in the field
of cell expressing eve.
Jaeger et al. (2004) Nature 430, 368.
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eve lessons
Regulatory regions can be divided into modular
units. Modularity of enhancers depends on local
activity of repressors. eve (and other) enhancer
sequences are subject to evolutionary
drift. Premier system for quantitative analysis.
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Outline 1. Definitions 2. eve - one
gene/multiple enhancers 3. Globin locus - one
enhancer/multiple genes 4. HOX genes - boundaries
memory modules 5. Enhancer-promoter trafficking
and boundary elements
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Enhancer 2
Enhancer 1
Locus control region (LCR)
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Beta globin genes in man mouse
embryonic fetal adult
Fu et al. (2002) Exp Cell Res 278, 1-11
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Binding of tissue-specific and general transcripti
on factors create altered chromatin structure
(DNAseI hypersensitivity)
Dekker (2003) TIBS 28, 277.
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Spreading model
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Dekker (2003) TIBS 28, 277.
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Dekker (2003) TIBS 28, 277.
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Carter (2002) Nat Gen 32623.
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Stochastic regulatory switching
Wijgerde et al. (1995) Nature 377, 209.
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Beta globin lessons
Regulatory regions can be very large Roles in
chromatin modification and direct gene
activation Transcription of noncoding regions -
cause or effect? Sequential activation of gene
cluster
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Outline 1. Definitions 2. eve - one
gene/multiple enhancers 3. Globin locus - one
enhancer/multiple genes 4. HOX genes - boundaries
memory modules 5. Enhancer-promoter trafficking
and boundary elements
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Homeosis - William Bateson
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Genetic and molecular identification of HOX genes
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Evolutionarily conserved (duplications,
losses) Role in specification of segmented
tissues Anterior-posterior expression colinear
with gene order 5-3 Link to morphological
diversification
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Multiple, complex regulatory regions controlling
Hox genes. Drosophila
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Expression of homeotic genes of the bithorax
complex
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Functional elements in transcriptional control
region
Abd-B
iab-5 iab-6 iab-7 iab-8
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Functional elements in transcriptional control
region
Abd-B
iab-5 iab-6 iab-7 iab-8
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Functional elements in transcriptional control
region
Boundary Elements
Mcp Fab-6 Fab-7 Fab-8
Abd-B
iab-5 iab-6 iab-7 iab-8
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Functional elements in transcriptional control
region
Boundary Elements
Mcp Fab-6 Fab-7 Fab-8
Abd-B
iab-5 iab-6 iab-7 iab-8
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Functional elements in transcriptional control
region
Promoter-targeting sequences
Mcp Fab-6? Fab-7 Fab-8
Abd-B
iab-5 iab-6 iab-7 iab-8
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Memory Modules
Transient activation or repression, followed
by action of Polycomb or Trithorax group proteins
Arnosti (2002) Insect Biochem Mol Bio 32 1257
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Blue lines indicate predicted genes
This cluster of genes is situated in an island
lacking junk DNA.
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Expression of HOX genes in crustaceans
Levine, Carroll
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HOX lessons Linear order of genes and regulatory
sequences important Enhancers, boundary
elements, promoter targeting sequences, and
memory modules combined to achieve fine
regulation Colinearity between physical layout
and anterior-posterior expression is still not
understood Variation in HOX expression linked to
evolutionary changes
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Outline 1. Definitions 2. eve - one
gene/multiple enhancers 3. Globin locus - one
enhancer/multiple genes 4. HOX genes - boundaries
memory modules 5. Enhancer-promoter trafficking
and boundary elements
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Traffic problems
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Enhancer-promoter specificity
Merli et al. (1996) Genes Dev. 101260
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rhomboid NEE
TATA
DPE
(nonselective)
ftz AE1, abdB IAB5
TATA
DPE
(selective)
Ohsutki and Levine
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Promoter-Enhancer specificity - is fidelity the
rule?
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Enhancer-promoter specificity lessons Cis-regulat
ory elements have a limited range, generally
preventing widespread cross-regulation Boundary
elements may contribute to enhancer-promoter
specificity- few documented cases Examples of
enhancer-promoter specificity exist Perhaps
cross-regulation is tolerated in many cases
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