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Evolution of the holozoan ribosome biogenesis regulon.

Brown SJ, Cole MD, Erives AJ - BMC Genomics (2008)

Bottom Line: These results show that this mode of regulation, characterized by an E(CG)-bearing core-promoter, is specific to almost all of the known genes involved in ribosome biogenesis in these genomes.Furthermore, a detailed analysis of 10 fungal genomes shows that this holozoan signature in RiBi genes is not found in hemiascomycete fungi, which evolved their own unique regulatory signature for the RiBi regulon.Furthermore, by comparing divergent bHLH repertoires, we conclude that regulation by Myc but not by other bHLH genes is responsible for the evolutionary maintenance of E(CG) sites across the RiBi suite of genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA. seth.brown@dartmouth.edu

ABSTRACT

Background: The ribosome biogenesis (RiBi) genes encode a highly-conserved eukaryotic set of nucleolar proteins involved in rRNA transcription, assembly, processing, and export from the nucleus. While the mode of regulation of this suite of genes has been studied in the yeast, Saccharomyces cerevisiae, how this gene set is coordinately regulated in the larger and more complex metazoan genomes is not understood.

Results: Here we present genome-wide analyses indicating that a distinct mode of RiBi regulation co-evolved with the E(CG)-binding, Myc:Max bHLH heterodimer complex in a stem-holozoan, the ancestor of both Metazoa and Choanoflagellata, the protozoan group most closely related to animals. These results show that this mode of regulation, characterized by an E(CG)-bearing core-promoter, is specific to almost all of the known genes involved in ribosome biogenesis in these genomes. Interestingly, this holozoan RiBi promoter signature is absent in nematode genomes, which have not only secondarily lost Myc but are marked by invariant cell lineages typically producing small body plans of 1000 somatic cells. Furthermore, a detailed analysis of 10 fungal genomes shows that this holozoan signature in RiBi genes is not found in hemiascomycete fungi, which evolved their own unique regulatory signature for the RiBi regulon.

Conclusion: These results indicate that a Myc regulon, which is activated in proliferating cells during normal development as well as during tumor progression, has primordial roots in the evolution of an inducible growth regime in a protozoan ancestor of animals. Furthermore, by comparing divergent bHLH repertoires, we conclude that regulation by Myc but not by other bHLH genes is responsible for the evolutionary maintenance of E(CG) sites across the RiBi suite of genes.

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E(CG) is a core promoter element of Drosophila ribosome biogenesis (RiBi) genes. (A) Fly RiBi genes (5 examples shown) generally possess three common features around the transcriptional start site (rightward pointing arrow) and upstream of the translational start (ATG). This distinct promoter architecture is characterized by a CG-core E-box (blue box), a specific E(CG) flanking motif (green box) and a coordinating cluster of sites matching the DNA Replication Element, DRE, (red boxes) spanning a distance less than 100 bp. The distance of E(CG) to the TSS for each gene is indicated above E(CG). G6375 corresponds to the pit gene, which is a known Myc target and an RiBi gene [18]. (B) This core promoter architecture identifies several functional groups of genes associated with RiBi (green circles). The number of genes is indicated for functional groups with more than 3 members. The sum of 151 genes (large circle) is the sum of all of the individual subfunctions with specific roles in Ribosome Biogenesis. The RiBi genes encode a variety of domains and protein folds including RNA-binding regions (RNP-1), C-terminal helicases, DEAD/DEAH box helicases, WD-40 repeats, ARM repeats, Histone-folds, AAA ATPases and many others [see Additional file 1]. (C) The results of genome queries in Drosophila for E(CG) type core promoters results in a highly significant enrichment of GO terms directly related to ribosome biogenesis (nucleolar, rRNA metabolism, rRNA binding, snoRNA complex, pseudouridine synthesis, ribosomal subunits, etc.)
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Figure 1: E(CG) is a core promoter element of Drosophila ribosome biogenesis (RiBi) genes. (A) Fly RiBi genes (5 examples shown) generally possess three common features around the transcriptional start site (rightward pointing arrow) and upstream of the translational start (ATG). This distinct promoter architecture is characterized by a CG-core E-box (blue box), a specific E(CG) flanking motif (green box) and a coordinating cluster of sites matching the DNA Replication Element, DRE, (red boxes) spanning a distance less than 100 bp. The distance of E(CG) to the TSS for each gene is indicated above E(CG). G6375 corresponds to the pit gene, which is a known Myc target and an RiBi gene [18]. (B) This core promoter architecture identifies several functional groups of genes associated with RiBi (green circles). The number of genes is indicated for functional groups with more than 3 members. The sum of 151 genes (large circle) is the sum of all of the individual subfunctions with specific roles in Ribosome Biogenesis. The RiBi genes encode a variety of domains and protein folds including RNA-binding regions (RNP-1), C-terminal helicases, DEAD/DEAH box helicases, WD-40 repeats, ARM repeats, Histone-folds, AAA ATPases and many others [see Additional file 1]. (C) The results of genome queries in Drosophila for E(CG) type core promoters results in a highly significant enrichment of GO terms directly related to ribosome biogenesis (nucleolar, rRNA metabolism, rRNA binding, snoRNA complex, pseudouridine synthesis, ribosomal subunits, etc.)

Mentions: By searching for novel motifs, we first noted that the flanks of the E(CG) site often match an extended consensus MAACACGTGYG (M = A/C, Y = C/T). Three out of every four core promoters that contain this extended E(CG) consensus map to RiBi genes (Fig. 1A). As a negative control for the specificity of the flanking sequence, we also searched the entire genome with an E(CG) motif in which the flanking pattern was maximally divergent from the observed, RiBi-specific, CG-core E-box flanking pattern. This "anti-flank" E(CG) motif, KKYCACGTGRMK (K = G/T, R = A/G), maps to almost 3-fold more sites than the extended E(CG) consensus, but nonetheless is absent from the core promoters of known nucleolar or RiBi orthologs (data not shown).


Evolution of the holozoan ribosome biogenesis regulon.

Brown SJ, Cole MD, Erives AJ - BMC Genomics (2008)

E(CG) is a core promoter element of Drosophila ribosome biogenesis (RiBi) genes. (A) Fly RiBi genes (5 examples shown) generally possess three common features around the transcriptional start site (rightward pointing arrow) and upstream of the translational start (ATG). This distinct promoter architecture is characterized by a CG-core E-box (blue box), a specific E(CG) flanking motif (green box) and a coordinating cluster of sites matching the DNA Replication Element, DRE, (red boxes) spanning a distance less than 100 bp. The distance of E(CG) to the TSS for each gene is indicated above E(CG). G6375 corresponds to the pit gene, which is a known Myc target and an RiBi gene [18]. (B) This core promoter architecture identifies several functional groups of genes associated with RiBi (green circles). The number of genes is indicated for functional groups with more than 3 members. The sum of 151 genes (large circle) is the sum of all of the individual subfunctions with specific roles in Ribosome Biogenesis. The RiBi genes encode a variety of domains and protein folds including RNA-binding regions (RNP-1), C-terminal helicases, DEAD/DEAH box helicases, WD-40 repeats, ARM repeats, Histone-folds, AAA ATPases and many others [see Additional file 1]. (C) The results of genome queries in Drosophila for E(CG) type core promoters results in a highly significant enrichment of GO terms directly related to ribosome biogenesis (nucleolar, rRNA metabolism, rRNA binding, snoRNA complex, pseudouridine synthesis, ribosomal subunits, etc.)
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Figure 1: E(CG) is a core promoter element of Drosophila ribosome biogenesis (RiBi) genes. (A) Fly RiBi genes (5 examples shown) generally possess three common features around the transcriptional start site (rightward pointing arrow) and upstream of the translational start (ATG). This distinct promoter architecture is characterized by a CG-core E-box (blue box), a specific E(CG) flanking motif (green box) and a coordinating cluster of sites matching the DNA Replication Element, DRE, (red boxes) spanning a distance less than 100 bp. The distance of E(CG) to the TSS for each gene is indicated above E(CG). G6375 corresponds to the pit gene, which is a known Myc target and an RiBi gene [18]. (B) This core promoter architecture identifies several functional groups of genes associated with RiBi (green circles). The number of genes is indicated for functional groups with more than 3 members. The sum of 151 genes (large circle) is the sum of all of the individual subfunctions with specific roles in Ribosome Biogenesis. The RiBi genes encode a variety of domains and protein folds including RNA-binding regions (RNP-1), C-terminal helicases, DEAD/DEAH box helicases, WD-40 repeats, ARM repeats, Histone-folds, AAA ATPases and many others [see Additional file 1]. (C) The results of genome queries in Drosophila for E(CG) type core promoters results in a highly significant enrichment of GO terms directly related to ribosome biogenesis (nucleolar, rRNA metabolism, rRNA binding, snoRNA complex, pseudouridine synthesis, ribosomal subunits, etc.)
Mentions: By searching for novel motifs, we first noted that the flanks of the E(CG) site often match an extended consensus MAACACGTGYG (M = A/C, Y = C/T). Three out of every four core promoters that contain this extended E(CG) consensus map to RiBi genes (Fig. 1A). As a negative control for the specificity of the flanking sequence, we also searched the entire genome with an E(CG) motif in which the flanking pattern was maximally divergent from the observed, RiBi-specific, CG-core E-box flanking pattern. This "anti-flank" E(CG) motif, KKYCACGTGRMK (K = G/T, R = A/G), maps to almost 3-fold more sites than the extended E(CG) consensus, but nonetheless is absent from the core promoters of known nucleolar or RiBi orthologs (data not shown).

Bottom Line: These results show that this mode of regulation, characterized by an E(CG)-bearing core-promoter, is specific to almost all of the known genes involved in ribosome biogenesis in these genomes.Furthermore, a detailed analysis of 10 fungal genomes shows that this holozoan signature in RiBi genes is not found in hemiascomycete fungi, which evolved their own unique regulatory signature for the RiBi regulon.Furthermore, by comparing divergent bHLH repertoires, we conclude that regulation by Myc but not by other bHLH genes is responsible for the evolutionary maintenance of E(CG) sites across the RiBi suite of genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA. seth.brown@dartmouth.edu

ABSTRACT

Background: The ribosome biogenesis (RiBi) genes encode a highly-conserved eukaryotic set of nucleolar proteins involved in rRNA transcription, assembly, processing, and export from the nucleus. While the mode of regulation of this suite of genes has been studied in the yeast, Saccharomyces cerevisiae, how this gene set is coordinately regulated in the larger and more complex metazoan genomes is not understood.

Results: Here we present genome-wide analyses indicating that a distinct mode of RiBi regulation co-evolved with the E(CG)-binding, Myc:Max bHLH heterodimer complex in a stem-holozoan, the ancestor of both Metazoa and Choanoflagellata, the protozoan group most closely related to animals. These results show that this mode of regulation, characterized by an E(CG)-bearing core-promoter, is specific to almost all of the known genes involved in ribosome biogenesis in these genomes. Interestingly, this holozoan RiBi promoter signature is absent in nematode genomes, which have not only secondarily lost Myc but are marked by invariant cell lineages typically producing small body plans of 1000 somatic cells. Furthermore, a detailed analysis of 10 fungal genomes shows that this holozoan signature in RiBi genes is not found in hemiascomycete fungi, which evolved their own unique regulatory signature for the RiBi regulon.

Conclusion: These results indicate that a Myc regulon, which is activated in proliferating cells during normal development as well as during tumor progression, has primordial roots in the evolution of an inducible growth regime in a protozoan ancestor of animals. Furthermore, by comparing divergent bHLH repertoires, we conclude that regulation by Myc but not by other bHLH genes is responsible for the evolutionary maintenance of E(CG) sites across the RiBi suite of genes.

Show MeSH
Related in: MedlinePlus