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Evolution of lysine acetylation in the RNA polymerase II C-terminal domain.

Simonti CN, Pollard KS, Schröder S, He D, Bruneau BG, Ott M, Capra JA - BMC Evol. Biol. (2015)

Bottom Line: Genes occupied and regulated by acRPB1 show significant enrichment for evolutionary origins in the early history of eukaryotes through early vertebrates.The functional analysis of genes regulated by acRPB1 highlight functions involved in the origin of and diversification of complex Metazoa.This suggests that acRPB1 may have played a role in the success of animals.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, 37232, USA. corinne.n.simonti@vanderbilt.edu.

ABSTRACT

Background: RPB1, the largest subunit of RNA polymerase II, contains a highly modifiable C-terminal domain (CTD) that consists of variations of a consensus heptad repeat sequence (Y1S2P3T4S5P6S7). The consensus CTD repeat motif and tandem organization represent the ancestral state of eukaryotic RPB1, but across eukaryotes CTDs show considerable diversity in repeat organization and sequence content. These differences may reflect lineage-specific CTD functions mediated by protein interactions. Mammalian CTDs contain eight non-consensus repeats with a lysine in the seventh position (K7). Posttranslational acetylation of these sites was recently shown to be required for proper polymerase pausing and regulation of two growth factor-regulated genes.

Results: To investigate the origins and function of RPB1 CTD acetylation (acRPB1), we computationally reconstructed the evolution of the CTD repeat sequence across eukaryotes and analyzed the evolution and function of genes dysregulated when acRPB1 is disrupted. Modeling the evolutionary dynamics of CTD repeat count and sequence content across diverse eukaryotes revealed an expansion of the CTD in the ancestors of Metazoa. The new CTD repeats introduced the potential for acRPB1 due to the appearance of distal repeats with lysine at position seven. This was followed by a further increase in the number of lysine-containing repeats in developmentally complex clades like Deuterostomia. Mouse genes enriched for acRPB1 occupancy at their promoters and genes with significant expression changes when acRPB1 is disrupted are enriched for several functions, such as growth factor response, gene regulation, cellular adhesion, and vascular development. Genes occupied and regulated by acRPB1 show significant enrichment for evolutionary origins in the early history of eukaryotes through early vertebrates.

Conclusions: Our combined functional and evolutionary analyses show that RPB1 CTD acetylation was possible in the early history of animals, and that the K7 content of the CTD expanded in specific developmentally complex metazoan lineages. The functional analysis of genes regulated by acRPB1 highlight functions involved in the origin of and diversification of complex Metazoa. This suggests that acRPB1 may have played a role in the success of animals.

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Genes regulated by acRPB1 are significantly enriched for evolutionary origins from early eukaryotes through early animals. ProteinHistorian analysis of the evolutionary origins of acRPB1 enriched genes (A) and acRPB1 dysregulated genes (B) compared with relevant background gene sets. Each bar gives the difference between the proportion of genes of interest and background genes originating in the last common ancestor of a given taxon (* = p < 0.05, ** = p < 0.01, *** = p < 0.001, all Bonferroni corrected). The proportion of genes of interest with origins in each taxon is given along the x-axis. For example, 18% of the acRPB1 enriched genes likely appeared between the origin of Opisthokonta and Bilateria, and this is significantly more (~7%, p < 0.001) than expected from the background of all genes with occupancy data.
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Fig4: Genes regulated by acRPB1 are significantly enriched for evolutionary origins from early eukaryotes through early animals. ProteinHistorian analysis of the evolutionary origins of acRPB1 enriched genes (A) and acRPB1 dysregulated genes (B) compared with relevant background gene sets. Each bar gives the difference between the proportion of genes of interest and background genes originating in the last common ancestor of a given taxon (* = p < 0.05, ** = p < 0.01, *** = p < 0.001, all Bonferroni corrected). The proportion of genes of interest with origins in each taxon is given along the x-axis. For example, 18% of the acRPB1 enriched genes likely appeared between the origin of Opisthokonta and Bilateria, and this is significantly more (~7%, p < 0.001) than expected from the background of all genes with occupancy data.

Mentions: Evolutionary analysis by ProteinHistorian showed that acRPB1-enriched genes had a significantly different age distribution from all genes with occupancy data (Figure 4A, p ≈ 0, Mann–Whitney U test). The acRPB1-enriched genes were significantly enriched for origins on the branch from Opisthokonta to Bilateria (18.3% vs. 11.8%, p < 0.001), the branch from Chordata to Euteleostomi (19.2% vs. 13.9%, p < 0.01), and the ancestral eukaryote branch (14.8% vs. 7.7%, p < 0.001). (Note that due to the species present in the ProteinHistorian database, the resolution of the protein age analysis is not as high as the CTD repeat analysis.) Comparing the evolutionary origins of dysregulated genes to the background of all genes on the array revealed a similar age pattern (Figure 4B; p = 1.4E-52). In particular, the dysregulated genes were enriched for origins in the ancestral eukaryote, the early history of animals (Opisthokonta to Bilateria branch), and shortly thereafter on the Deuterostomia to Chordata and Chordata to Euteleostomi branches (p < 0.001 for each). Both gene sets showed consistent depletion of genes born after the origin of amniotes. Thus, two independent ways of defining genes influenced by acRPB1 underscore a potential role for K7 acetylation in regulating RNA polymerase II function at genes that were present as animal multicellularity developed and diversified (Figure 4).Figure 4


Evolution of lysine acetylation in the RNA polymerase II C-terminal domain.

Simonti CN, Pollard KS, Schröder S, He D, Bruneau BG, Ott M, Capra JA - BMC Evol. Biol. (2015)

Genes regulated by acRPB1 are significantly enriched for evolutionary origins from early eukaryotes through early animals. ProteinHistorian analysis of the evolutionary origins of acRPB1 enriched genes (A) and acRPB1 dysregulated genes (B) compared with relevant background gene sets. Each bar gives the difference between the proportion of genes of interest and background genes originating in the last common ancestor of a given taxon (* = p < 0.05, ** = p < 0.01, *** = p < 0.001, all Bonferroni corrected). The proportion of genes of interest with origins in each taxon is given along the x-axis. For example, 18% of the acRPB1 enriched genes likely appeared between the origin of Opisthokonta and Bilateria, and this is significantly more (~7%, p < 0.001) than expected from the background of all genes with occupancy data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4362643&req=5

Fig4: Genes regulated by acRPB1 are significantly enriched for evolutionary origins from early eukaryotes through early animals. ProteinHistorian analysis of the evolutionary origins of acRPB1 enriched genes (A) and acRPB1 dysregulated genes (B) compared with relevant background gene sets. Each bar gives the difference between the proportion of genes of interest and background genes originating in the last common ancestor of a given taxon (* = p < 0.05, ** = p < 0.01, *** = p < 0.001, all Bonferroni corrected). The proportion of genes of interest with origins in each taxon is given along the x-axis. For example, 18% of the acRPB1 enriched genes likely appeared between the origin of Opisthokonta and Bilateria, and this is significantly more (~7%, p < 0.001) than expected from the background of all genes with occupancy data.
Mentions: Evolutionary analysis by ProteinHistorian showed that acRPB1-enriched genes had a significantly different age distribution from all genes with occupancy data (Figure 4A, p ≈ 0, Mann–Whitney U test). The acRPB1-enriched genes were significantly enriched for origins on the branch from Opisthokonta to Bilateria (18.3% vs. 11.8%, p < 0.001), the branch from Chordata to Euteleostomi (19.2% vs. 13.9%, p < 0.01), and the ancestral eukaryote branch (14.8% vs. 7.7%, p < 0.001). (Note that due to the species present in the ProteinHistorian database, the resolution of the protein age analysis is not as high as the CTD repeat analysis.) Comparing the evolutionary origins of dysregulated genes to the background of all genes on the array revealed a similar age pattern (Figure 4B; p = 1.4E-52). In particular, the dysregulated genes were enriched for origins in the ancestral eukaryote, the early history of animals (Opisthokonta to Bilateria branch), and shortly thereafter on the Deuterostomia to Chordata and Chordata to Euteleostomi branches (p < 0.001 for each). Both gene sets showed consistent depletion of genes born after the origin of amniotes. Thus, two independent ways of defining genes influenced by acRPB1 underscore a potential role for K7 acetylation in regulating RNA polymerase II function at genes that were present as animal multicellularity developed and diversified (Figure 4).Figure 4

Bottom Line: Genes occupied and regulated by acRPB1 show significant enrichment for evolutionary origins in the early history of eukaryotes through early vertebrates.The functional analysis of genes regulated by acRPB1 highlight functions involved in the origin of and diversification of complex Metazoa.This suggests that acRPB1 may have played a role in the success of animals.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, 37232, USA. corinne.n.simonti@vanderbilt.edu.

ABSTRACT

Background: RPB1, the largest subunit of RNA polymerase II, contains a highly modifiable C-terminal domain (CTD) that consists of variations of a consensus heptad repeat sequence (Y1S2P3T4S5P6S7). The consensus CTD repeat motif and tandem organization represent the ancestral state of eukaryotic RPB1, but across eukaryotes CTDs show considerable diversity in repeat organization and sequence content. These differences may reflect lineage-specific CTD functions mediated by protein interactions. Mammalian CTDs contain eight non-consensus repeats with a lysine in the seventh position (K7). Posttranslational acetylation of these sites was recently shown to be required for proper polymerase pausing and regulation of two growth factor-regulated genes.

Results: To investigate the origins and function of RPB1 CTD acetylation (acRPB1), we computationally reconstructed the evolution of the CTD repeat sequence across eukaryotes and analyzed the evolution and function of genes dysregulated when acRPB1 is disrupted. Modeling the evolutionary dynamics of CTD repeat count and sequence content across diverse eukaryotes revealed an expansion of the CTD in the ancestors of Metazoa. The new CTD repeats introduced the potential for acRPB1 due to the appearance of distal repeats with lysine at position seven. This was followed by a further increase in the number of lysine-containing repeats in developmentally complex clades like Deuterostomia. Mouse genes enriched for acRPB1 occupancy at their promoters and genes with significant expression changes when acRPB1 is disrupted are enriched for several functions, such as growth factor response, gene regulation, cellular adhesion, and vascular development. Genes occupied and regulated by acRPB1 show significant enrichment for evolutionary origins in the early history of eukaryotes through early vertebrates.

Conclusions: Our combined functional and evolutionary analyses show that RPB1 CTD acetylation was possible in the early history of animals, and that the K7 content of the CTD expanded in specific developmentally complex metazoan lineages. The functional analysis of genes regulated by acRPB1 highlight functions involved in the origin of and diversification of complex Metazoa. This suggests that acRPB1 may have played a role in the success of animals.

Show MeSH
Related in: MedlinePlus