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Evolution of the Holozoan Ribosome Biogenesis Regulon

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Evolution of the Holozoan Ribosome Biogenesis Regulon Dartmouth College Dartmouth Digital Commons Dartmouth Scholarship Faculty Work 9-24-2008 Evolution of the Holozoan Ribosome Biogenesis Regulon Seth J. Brown Dartmouth College Michael D. Cole Dartmouth College Albert J. Erives Dartmouth College Follow this and additional works at: https://digitalcommons.dartmouth.edu/facoa Part of the Biology Commons, and the Genetics and Genomics Commons Dartmouth Digital Commons Citation Brown, Seth J.; Cole, Michael D.; and Erives, Albert J., "Evolution of the Holozoan Ribosome Biogenesis Regulon" (2008). Dartmouth Scholarship. 604. https://digitalcommons.dartmouth.edu/facoa/604 This Article is brought to you for free and open access by the Faculty Work at Dartmouth Digital Commons. It has been accepted for inclusion in Dartmouth Scholarship by an authorized administrator of Dartmouth Digital Commons. For more information, please contact [email protected]. BMC Genomics BioMed Central Research article Open Access Evolution of the holozoan ribosome biogenesis regulon Seth J Brown1, Michael D Cole*1,2 and Albert J Erives*3 Address: 1Department of Genetics, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA, 2Department of Pharmacology and Toxicology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA and 3Department of Biological Sciences, Dartmouth College, Hanover, NH 03755, USA Email: Seth J Brown - [email protected]; Michael D Cole* - [email protected]; Albert J Erives* - [email protected] * Corresponding authors Published: 24 September 2008 Received: 19 June 2008 Accepted: 24 September 2008 BMC Genomics 2008, 9:442 doi:10.1186/1471-2164-9-442 This article is available from: http://www.biomedcentral.com/1471-2164/9/442 © 2008 Brown et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. Background proteins are involved both in this enzymatic processing as Ribosome biogenesis (RiBi) is a primary function of the well in assisting with proper rRNA folding to produce nucleolus [1-3]. In the nucleolus, rRNA molecules are syn- functional ribosomal subunits [1]. Synthesizing func- thesized as precursors by DNA-directed RNA Pol I and Pol tional ribosomes requires immense coordination because III. Nascent rRNAs then undergo extensive chemical mod- gene products from all three DNA-dependent RNA ifications and RNA cleavage reactions. Numerous RiBi polymerases are required to ensure proper stoichiometry Page 1 of 13 (page number not for citation purposes) BMC Genomics 2008, 9:442 http://www.biomedcentral.com/1471-2164/9/442 of ribosomal components. This level of co-regulation is ize a co-regulated RiBi gene set definable by a shared reg- likely to be controlled through a highly-specific DNA sig- ulatory signature, a component of which would be the nature as seen in other gene regulatory systems [4]. Such a Myc-Max binding site E(CG). A priori, we had no reason to signature would allow the appropriate factors to co-ordi- expect whether a common regulatory signature would be nately regulate the RiBi genes as a distinct regulon. For found across the large number of known ribosome bio- example, in the yeast Saccharomyces cerevisiae two impor- genesis genes or whether such a signature would be lim- tant regulatory motifs consisting of the PAC (polymerase ited to only a subset (i.e. the sensitivity of the postulated A and C) and RRPE (Ribosomal RNA Processing Element) signature for RiBi genes). Furthermore, we set no expecta- motifs have been identified in RiBi genes [5-7]. In animals tion on whether this signature would necessarily be no known factor or motif is known to coordinate the present or absent in other non-RiBi genes devoted to cell entire RiBi set. However, the metazoan transcription fac- growth or other functions (i.e. the specificity of the postu- tor Myc has been found to target at least some RiBi genes. lated signature for RiBi genes). For this purpose, we chose the Drosophila melanogaster genome because of its rela- Myc is a bHLH DNA-binding protein present in animals tively compact size and absence of genome wide duplica- where it plays an important role in cell growth and prolif- tions characteristic of vertebrates. Both of these properties eration by regulating gene expression during development facilitate the identification of a sequence signature and the and tumorigenesis [8-10]. Myc functions by heterodimer- characterization of its sensitivity and specificity for entire izing with its obligate partner Max to bind the sequence biological functions because they simplify the ability to 5'-CACGTG [a CG-core E-box, or E(CG)] and transactivate conduct and interpret computational queries of genome target genes [11-14]. Previous studies have implicated the sequence. Myc transcription factor in rRNA transcription [15-17], but the possibility that Myc could directly regulate the Having identified the list of genes in this fly regulon we hundreds of gene products involved in RiBi, as opposed to would then utilize the many available eukaryotic genome a few early genes or key steps [18-20], has not been inves- sequences to identify shared sequence signatures associ- tigated. Also unknown is when such an RiBi circuit or ated with this regulon in each genome. Because of the other non-RiBi targets of Myc may have evolved and highly conserved nature of the protein functions associ- whether it was in the most recent common ancestor of ated with ribosome biogenesis, it is likely that this list of Bilateria (protostomes and deuterostomes), Metazoa genes would remain co-regulated in other genomes (animals), Holozoa (Metazoa + choanoflagellates), despite evolution of the regulatory signatures associated Opisthokonta (Holozoa + fungi), or Eukaryota. with this regulon. Here, we use a multi-genomic approach to show that the E(CG) is highly specific to the fly RiBi regulon vast majority of genes implicated in ribosome biogenesis An overwhelming majority of confirmed Myc targets con- are associated with E(CG)-bearing core promoters in all tain E(CG) near the transcriptional start site (TSS) [19]. holozoan genomes containing Myc, and thus constitutes We therefore examined all fly genes with promoter proxi- a uniquely holozoan RiBi regulon. Max, Mad, and Mnt, all mal E(CG) sites to determine whether they were related by members of the Myc bHLH superfamily, are all either a common cellular function. We searched the Drosophila insufficient or dispensable in explaining the correlation of melanogaster genome and identified only 390 promoter E(CG) with RiBi as revealed by a comparison of multiple sequences containing an E(CG) site in the core promoter eukaryotic genomes, which differ in their bHLH reper- region (160 bp centered around +1) out of 20,468 anno- toires. Thus, in addition to known RiBi targets of Myc [18- tated transcripts (14,752 genes). Remarkably, these genes 20] and the similar growth defects of both RiBi and myc include most proteins known to be involved throughout mutant alleles [8-10,18,20,21], our comparative genomic ribosome biogenesis [see Additional file 1]. To examine results suggest that the characteristic RiBi E(CG) core pro- the relationship between the E(CG) motif and ribosome moter architecture co-evolved with a proto-Myc:Max com- biogenesis in more detail, we used Gene Ontology (GO) plex in a unicellular holozoan ancestor. This is consistent classification of the yeast genome to map 121 fly with the metabolic evolution of a unique, Myc-Max regu- orthologs
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