Transcript Gen660_Lecture12B_NetworkEvo_2014

How do regulatory networks evolve?
Module = group of genes co-regulated by the same regulatory system
* Evolution of individual gene targets
Gain or loss of genes from a module
* Evolution of activating signals
Change in responsiveness but not regulators
* Wholesale evolution of the entire module
Transcription factor sites occur upstream of totally different genes,
responding to totally different signals
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How do regulatory networks evolve?
Short time-scales: gene target turnover (gain and loss)
Time
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Science 2007
ChIP-chip of two cooperatively-acting TFs in 3 species
(S. cerevisiae, S. mikatae, S. bayanus ~20 my diverged)
Tec1
Ste12
Pseudohyphal growth
Genes
Ste12
Ste12
Mating genes
(haploid cells only)
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Only ~20% of orthologous regions bound in all 3 species
Scer
Ste12 380
Smik
167
Sbay
250 21% bound in all 3 species
Tec1 348
185
126 20% bound in all 3 species
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* non-S. cer but otherwise conserved binding: enriched for Mating Genes
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Borneman et al. Science 2007
Only 20% of bound fragments conserved over 20 my
(75% of these have underlying binding sites conserved)
Tec1
Ste12
Substantial ‘rewiring’ of transcriptional circuits:
* Gain and loss of individual gene targets
* S.cer evolution of the module of mating genes
How common will these trends be? Different trends for different functional processes?
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How common will these trends be? Different trends for different functional processes?
PLoS Biol. April 2010
ChIP-chip of 6 developmental TFs in D. mel vs. D. yakuba (5 my)
* only 1-5% of genes are variable targets (gene target turnover)
* lots of evidence of TF binding site turnover
within CONSERVED target regions
Cell. March 2013
40% mouse TF binding sites conserved over < 6my
Nature. March 2010
Science April 2010
ChIP-chip’d Ste12 in 43 S. cerevisiae segregants
Science. 2010
10-22% of TF binding is conserved in mammals
(diverged ~80 my)
ChIP-seq (NFB and RNA-Pol II) and RNA-seq in
10 humans from 3 different populations
Lots of variation (up to 25% variation in binding levels)
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How do regulatory networks evolve?
Short time-scales: gene target turnover (gain and loss)
Cooption of existing network
Time
Evolved
Responsiveness
Time
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Ancestral GAL control likely by Cph1 … S. cerevisiae lineage picked up Gal4 and Mig1 sites upstream of GAL genes
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In addition to changes in upstream cis-elements …
Major changes in the Gal4 transcription factor & upstream along S. cerevisiae lineage:
* Gained a domain that interacts with the Galactose-responsive Gal80 protein
* Other changes in the upstream response (Gal1-Gal3 duplication) contributed
to sensitized pathway
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How do regulatory networks evolve?
Short time-scales: gene target turnover (gain and loss)
Evolved
Responsiveness
Time
Time
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How do regulatory networks evolve?
Sub/neo-functionalization through TF duplication & divergence
TF duplication
Time
Evolved TF sensitivity, binding specificity,
and ultimately targets
Time
Gene targets can also duplicate
(especially in WGD)
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Example: Arg80 and Mcm1 duplication
Tuch et al. 2008. PLoS Biol.
Mcm1 is a co-factor that works with many different site-specific TFs
Tuch. et al. performed ChIP-chip on Mcm1 orthologs in multiple fungi.
* Found dramatic differences in inferred Mcm1-TF interactions and modules
One case in particular: Arginine biosynthesis genes
Time (>150 my)
Mcm1 + Arg81
at arg genes is ancestral
Duplication of Mcm1
(Arg80) at WGD
Loss of Mcm1 binding at arg genes
Presumably taken over by Arg80
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How do regulatory networks evolve?
Conundrum:
Clearest cases of regulatory switches are often for highly co-regulated genes,
whose co-regulation is high conserved.
If co-regulation is so important, then how can tolerate many independent changes
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in upstream cis-elements?
Here they ChIP’d 6 TFs implicated in
RP regulation in
S. cerevisiae and/or C. albicans
Ifh1-Fhl1 co-activators are conserved
in Sc-Ca (>200 my)
Required co-factors have evolved:
Hmo1 and Rap1 required for Ifh1-Fhl1 binding
in S. cerevisiae
* Hmo1 is a ‘generalist’ in C. albicans
In C. albicans, Cbf1 (generalist) and
Tbf1 (specialist) are required for
Ifh1-Fhl1 binding
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* They propose that ‘generalist’ factors
can readily ‘specialize’ to regulate
a specific module
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Figure 6
* Species-specific connection of regulons:
selection for alternate co-regulation
* They propose that ‘generalist’ factors
can readily ‘specialize’ to regulate
a specific module
* Species-specific connection of regulons:
selection for alternate co-regulation
* Co-evolution of binding sites AND
interactions of regulators
* They propose cycles of neutral
accumulation of mutations (and binding
sites) followed by deleterious mutation that
is rapidly ‘corrected’ to rebalance coregulation
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They raise the question:
Is wholesale rewiring common
to all modules
Or
facilitated by
very strong pressures to keep
genes co-regulated?
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