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How do regulatory networks evolve?

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

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How do regulatory networks evolve?

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  1. 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

  2. How do regulatory networks evolve? Short time-scales: gene target turnover (gain and loss) Time

  3. Science 2007 ChIP-chip of two cooperatively-acting TFs in 3 species (S. cerevisiae, S. mikatae, S. bayanus ~20 my diverged) Tec1 Ste12 Ste12 Ste12 Pseudohyphal growth Genes Mating genes (haploid cells only)

  4. Only ~20% of orthologous regions bound in all 3 species Scer Smik Sbay Ste12 Tec1 380 167 250 21% bound in all 3 species 20% bound in all 3 species 348 185 126

  5. * non-S. cer but otherwise conserved binding: enriched for Mating Genes

  6. 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?

  7. How common will these trends be? Different trends for different functional processes? Cell. March 2013 PLoS Biol. April 2010 40% mouse TF binding sites conserved over < 6my 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 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)

  8. How do regulatory networks evolve? Short time-scales: gene target turnover (gain and loss) Cooption of existing network Evolved Responsiveness Time Time

  9. Ancestral GAL control likely by Cph1 … S. cerevisiae lineage picked up Gal4 and Mig1 sites upstream of GAL genes

  10. 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

  11. How do regulatory networks evolve? Short time-scales: gene target turnover (gain and loss) Evolved Responsiveness Time Time

  12. How do regulatory networks evolve? Sub/neo-functionalization through TF duplication & divergence Evolved TF sensitivity, binding specificity, and ultimately targets TF duplication Time Time Gene targets can also duplicate (especially in WGD)

  13. 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

  14. 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 in upstream cis-elements?

  15. 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

  16. * They propose that ‘generalist’ factors can readily ‘specialize’ to regulate a specific module

  17. Figure 6 * Species-specific connection of regulons: selection for alternate co-regulation

  18. * 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 co-regulation

  19. 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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