Deletion of ribosomal protein genes is a common vulnerability in human cancer, particularly in concert with TP53 mutation
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Björn Nilsson
PROVIDER: E-MTAB-5450 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Ribosomal proteins are essential to life. While the functions of ribosomal protein-encoding genes (RPGs) are highly conserved, the evolution of their regulatory mechanisms is remarkably dynamic. In Saccharomyces cerevisiae, RPGs are unusual in that they are commonly present as two highly similar gene copies and that they are over-represented among intron-containing genes. To investigate the role of introns in the regulation of RPG expression, we constructed 16 S. cerevisiae strains with precise deletions of RPG introns. We found that several yeast introns function to repress rather than to increase steady-state mRNA levels. Among these, the RPS9A and RPS9B introns were required for cross-regulation of the two paralogous gene copies, which is consistent with the duplication of an autoregulatory circuit.
2012-03-01 | GSE35541 | GEO
Project description:Ribosomal proteins are essential to life. While the functions of ribosomal protein-encoding genes (RPGs) are highly conserved, the evolution of their regulatory mechanisms is remarkably dynamic. In Saccharomyces cerevisiae, RPGs are unusual in that they are commonly present as two highly similar gene copies and that they are over-represented among intron-containing genes. To investigate the role of introns in the regulation of RPG expression, we constructed 16 S. cerevisiae strains with precise deletions of RPG introns. We found that several yeast introns function to repress rather than to increase steady-state mRNA levels. Among these, the RPS9A and RPS9B introns were required for cross-regulation of the two paralogous gene copies, which is consistent with the duplication of an autoregulatory circuit. Splicing specific microarrays were used to assess the genome-wide defects in gene expression and pre-mRNA splicing that result from a deletion of a single ribosomal protein gene intron.
2012-03-01 | E-GEOD-35541 | biostudies-arrayexpress
Project description:In this study, we elucidate the common logic of the RPGs regulatory network by evaluating both the architecture and activity of promoters under conditions of stress or modulation of TF levels, and we identified the proteins regulating the activity of promoters lacking Rap1 binding, thus demonstrating that RPG co-regulation requires the complementary action of two different mechanisms involving both Ifh1 and Sfp1.
2020-11-27 | GSE155235 | GEO
Project description:Cell growth is well defined for the late (post-embryonic) stages of development, but evidence for early (embryonic) cell growth during post-mitotic morphogenesis is quite limited. Here, we identify early cell growth as a key characteristic of Drosophila embryonic salivary gland (SG) tubulogenesis. A BTB/POZ domain nuclear factor, Ribbon (Rib), mediates early cell growth without affecting endoreplication. Rib binds the transcription start site of nearly every SG-expressed ribosomal protein gene (RPG), and is required for full expression of all RPGs tested. Rib binding to RPG enhancers is, however, weak and not sequence-specific, suggesting that specificity is achieved through co-factor interactions. We demonstrate Rib’s ability to physically interact with each of the three known activators of RPG transcription. Surprisingly, Rib-dependent early cell growth in another tubular organ—the embryonic trachea—is not mediated by direct RPG transcription. Our results support a model for tissue-specific transcriptional regulation in early cell growth programs.
2022-02-15 | GSE181361 | GEO
Project description:The biological underpinnings of major depressive disorder (MDD) heterogeneity are unknown, in part due to the poor association between MDD models and clinical endpoints. We compared transcriptomic profiles of human postmortem MDD brain tissue and chronic variable stress (CVS)-exposed mice to identify orthologous genes. A downregulation of ribosomal protein genes (RPGs) and upregulation of associated RP pseudogenes in the prefrontal cortex of several independent cohorts from both human MDD and mouse CVS tissue prompted a seeded gene co-expression analysis using the RPGs altered in both groups. Downregulated RPGs were found to regulate synaptic changes in human MDD and mouse CVS through a RP pseudogene-driven mechanism. In vitro and in silico analysis further suggested that the inverse RPG/RP pseudogene association was a glucocorticoid-driven response and reversed during MDD remission. Thus, stress-induced alterations in RPGs may contribute to synaptic dysregulation in MDD, providing a mechanism for the variability in depression presentation.
2023-10-25 | GSE229905 | GEO
Project description:Ribosomal protein genes (RPGs) coding sequences are highly conserved along evolution; however, promoter features and the machinery involved in their transcriptional regulation are not. In eukaryotes, the main genomic elements and players involved in RPG transcriptional regulation have been mostly characterized in Saccharomyces cerevisiae. However, given the lack of evolutionary conservation of the yeast factors, studies in higher eukaryotes have focused on searching for differential enrichment of transcription factor-binding motifs within the RPG promoters. Among them, the palindromic motif TCTCGCGAGA, which is currently acknowledged as a ZBTB33/KAISO motif, also matches the genomic sequence bound by the protein kinase DYRK1A. DYRK1A, a member of the human family of DYRK kinases, fulfills many diverse functions by phosphorylating a broad set of proteins involved in different cellular processes. One of such functions is to be a chromatin-associated kinase capable of regulating gene expression. Here, we analyze in-depth the presence of DYRK1A at the promoters of human and mouse RPGs and explore its functional consequences. Our results indicate that DYRK1A is a positive regulator of RPGs’ expression at the transcriptional level, and that this effect could, at least in part, contribute to the global reduction in ribosome amounts and protein synthesis observed when DYRK1A is silenced. Therefore, our results further expand the functional spectrum of the kinase as a contributor to the regulation of cell growth in mammalian cells.
2024-05-22 | PXD022966 | Pride
Project description:In yeast, ribosome production is controlled transcriptionally by tight coregulation of the 138 ribosomal protein genes (RPGs). RPG promoters display limited sequence homology, and the molecular basis for their coregulation remains largely unknown. Here we identify two prevalent RPG promoter types, both characterized by upstream binding of the general transcription factor (TF) Rap1 followed by the RPG-specific Fhl1/Ifh1 pair, with one type also binding the HMG-B protein Hmo1. We show that the regulatory properties of the two promoter types are remarkably similar, suggesting that they are determined to a large extent by Rap1 and the Fhl1/Ifh1 pair. Rapid depletion experiments allowed us to define a hierarchy of TF binding in which Rap1 acts as a pioneer factor required for binding of all other TFs. We also uncovered unexpected features underlying recruitment of Fhl1, whose forkhead DNA-binding domain is not required for binding at most promoters, and Hmo1, whose binding is supported by repeated motifs. Finally, we describe unusually micrococcal nuclease (MNase)-sensitive nucleosomes at all RPG promoters, located between the canonical +1 and M-bM-^@M-^S1 nucleosomes, which coincide with sites of Fhl1/Ifh1 and Hmo1 binding. We speculate that these M-bM-^@M-^XM-bM-^@M-^XfragileM-bM-^@M-^YM-bM-^@M-^Y nucleosomes play an important role in regulating RPG transcriptional output. Genome-wide examination of binding sites for transcription factors controlling ribosomal protein genes expression and nucleosome positions in budding yeast cells
2014-10-01 | E-GEOD-61596 | biostudies-arrayexpress
Project description:In yeast, ribosome production is controlled transcriptionally by tight coregulation of the 138 ribosomal protein genes (RPGs). RPG promoters display limited sequence homology, and the molecular basis for their coregulation remains largely unknown. Here we identify two prevalent RPG promoter types, both characterized by upstream binding of the general transcription factor (TF) Rap1 followed by the RPG-specific Fhl1/Ifh1 pair, with one type also binding the HMG-B protein Hmo1. We show that the regulatory properties of the two promoter types are remarkably similar, suggesting that they are determined to a large extent by Rap1 and the Fhl1/Ifh1 pair. Rapid depletion experiments allowed us to define a hierarchy of TF binding in which Rap1 acts as a pioneer factor required for binding of all other TFs. We also uncovered unexpected features underlying recruitment of Fhl1, whose forkhead DNA-binding domain is not required for binding at most promoters, and Hmo1, whose binding is supported by repeated motifs. Finally, we describe unusually micrococcal nuclease (MNase)-sensitive nucleosomes at all RPG promoters, located between the canonical +1 and –1 nucleosomes, which coincide with sites of Fhl1/Ifh1 and Hmo1 binding. We speculate that these ‘‘fragile’’ nucleosomes play an important role in regulating RPG transcriptional output.
2014-10-01 | GSE61596 | GEO
Project description:Ribosomal protein genes (RPGs) coding sequences are highly conserved along evolution; however, promoter features and the machinery involved in their transcriptional regulation are not. In eukaryotes, the main genomic elements and players involved in RPG transcriptional regulation have been mostly characterized in Saccharomyces cerevisiae. However, given the lack of evolutionary conservation of the yeast factors, studies in higher eukaryotes have focused on searching for differential enrichment of transcription factor-binding motifs within the RPG promoters. Among them, the palindromic motif TCTCGCGAGA, which is currently acknowledged as a ZBTB33/KAISO motif, also matches the genomic sequence bound by the protein kinase DYRK1A. DYRK1A, a member of the human family of DYRK kinases, fulfills many diverse functions by phosphorylating a broad set of proteins involved in different cellular processes. One of such functions is to be a chromatin-associated kinase capable of regulating gene expression. Here, we analyze in-depth the presence of DYRK1A at the promoters of human and mouse RPGs and explore its functional consequences. Our results indicate that DYRK1A is a positive regulator of RPGs’ expression at the transcriptional level, and further expand the functional spectrum of the kinase as a contributor to the regulation of cell growth in mammalian cells.
2023-08-01 | GSE155808 | GEO
Project description:Ribosomal protein genes (RPGs) coding sequences are highly conserved along evolution; however, promoter features and the machinery involved in their transcriptional regulation are not. In eukaryotes, the main genomic elements and players involved in RPG transcriptional regulation have been mostly characterized in Saccharomyces cerevisiae. However, given the lack of evolutionary conservation of the yeast factors, studies in higher eukaryotes have focused on searching for differential enrichment of transcription factor-binding motifs within the RPG promoters. Among them, the palindromic motif TCTCGCGAGA, which is currently acknowledged as a ZBTB33/KAISO motif, also matches the genomic sequence bound by the protein kinase DYRK1A. DYRK1A, a member of the human family of DYRK kinases, fulfills many diverse functions by phosphorylating a broad set of proteins involved in different cellular processes. One of such functions is to be a chromatin-associated kinase capable of regulating gene expression. Here, we analyze in-depth the presence of DYRK1A at the promoters of human and mouse RPGs and explore its functional consequences. Our results indicate that DYRK1A is a positive regulator of RPGs’ expression at the transcriptional level, and further expand the functional spectrum of the kinase as a contributor to the regulation of cell growth in mammalian cells.
2023-08-01 | GSE155807 | GEO