Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1112448 | ENA |
REPOSITORIES: ENA
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Project description:Pseudouridylation (pseudouridine) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of pseudouridine remains poorly understood. Here, we show that a pseudouridine-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the pseudouridine ‘writer’ PUS7 modifies and activates a network of tRNA-derived fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translational regulation leading to high protein biosynthesis and abnormal germ layer specification. Dysregulation of PUS7 and tRFs in myeloid malignancies associates with altered translation rates, suggesting a role of pseudouridine in tumorigenesis. Our findings unveil a critical function of pseudouridine in directing translational control in stem cells with promisingly broad implications for human disease.
2018-04-09 | GSE101485 | GEO
Project description:Pseudouridine is the first discovered and the most frequent modification in RNA. However, its biological functions in physiology and human diseases are largely unknown. Here, we show that pseudouridine synthase PUS7 is differentially expressed in glioblastoma patient tissues verse non-tumor brain tissues, and highly expressed in patient brain-derived cancer stem cells, compared to normal brain-derived neural stem cells. Upregulated expression of PUS7 predicts worse survival in glioblastoma patients in multiple databases. Indeed, we show that PUS7 plays an important role in regulating the self-renewal and tumorigenesis of glioblastoma stem cells. Overexpression of the wild type but not the catalytically inactive PUS7 increases the growth and self-renewal of GSCs. In contrast, knockdown of PUS7 dramatically suppresses GSC growth, self-renewal and tumorigenesis. Mechanistically, knockdown of PUS7 activates interferon pathway through translational control of TYK2 via PUS7-regulated tRNAs. Moreover, we have identified chemical inhibitors for PUS7 in this study. These chemical compounds target pseudouridine modification and suppress GSC growth and tumorigenesis, providing a potential therapeutic tool for GBM treatment.
2021-06-18 | GSE147342 | GEO
Project description:Pseudouridine is the most abundant modification occurring on RNA, yet with the exception of a few well-studied RNA molecules little is known about the modified positions and their function(s). Here, we develop M-NM-(-seq, a method for transcriptome-wide quantitative mapping of pseudouridine. We validate M-NM-(-seq with synthetic spike-ins and de novo identification of the vast majority of previously reported pseudouridylated positions. M-NM-(-seq permits discovery of hundreds of novel pseudouridine modifications in human and yeast mRNAs and snoRNAs. Knockdown and knockout of pseudouridine synthases uncovers the cognate PUSs mediating pseudouridine catalysis at these individual novel sites and their target sequence features. In both human and yeast pseudouridine formation on mRNA depends on both site-specific PUSs M-bM-^@M-^S often guided by a specific sequence motif - and snoRNA-guided PUSs. Importantly, upon heat shock in yeast, Pus7-mediated pseudouridylation is induced at >200 sites in diverse mRNAs. Pus7 deletion in yeast leads to decreased recovery from heat shock and decreased RNA levels at otherwise pseudouridylated messages, suggesting a role for pseudouridine in enhancing transcript stability. Pseudouridine stoichiometries in rRNA are highly conserved from yeast to mammals, but are reduced in cells derived from dyskeratosis congenita patients, where the pseudouridine synthase DKC1 is mutated, compared to age matched controls. Our results establish pseudouridine as a ubiquitous and dynamic modification in mRNA, and provide a sensitive, quantitative and transcriptome-wide methodology to address its underlying mechanisms and function. Examination of m6A methylation in human Hek293 and A549 cell lines, in human embryonic stem cells (ESCs) undergoing differentiation to neural progenitor cells (NPCs), in OKMS inducible fibroblasts reprogrammed into iPSC, and upon knockdown of factors using siRNAs or shRNAs.
2014-09-11 | E-GEOD-60047 | biostudies-arrayexpress
Project description:PUS7, a pseudouridine synthase, plays a critical role in growth, self-renewal, and tumorigenesis of glioblastoma stem cells. We used RNA-seq to investigate the global gene expression regulated by PUS7 and identified downstream pathway of PUS7 in glioblastoma stem cells.
2021-06-18 | GSE147382 | GEO
Project description:Pseudouridine is the most abundant modification occurring on RNA, yet with the exception of a few well-studied RNA molecules little is known about the modified positions and their function(s). Here, we develop Ψ-seq, a method for transcriptome-wide quantitative mapping of pseudouridine. We validate Ψ-seq with synthetic spike-ins and de novo identification of the vast majority of previously reported pseudouridylated positions. Ψ-seq permits discovery of hundreds of novel pseudouridine modifications in human and yeast mRNAs and snoRNAs. Knockdown and knockout of pseudouridine synthases uncovers the cognate PUSs mediating pseudouridine catalysis at these individual novel sites and their target sequence features. In both human and yeast pseudouridine formation on mRNA depends on both site-specific PUSs – often guided by a specific sequence motif - and snoRNA-guided PUSs. Importantly, upon heat shock in yeast, Pus7-mediated pseudouridylation is induced at >200 sites in diverse mRNAs. Pus7 deletion in yeast leads to decreased recovery from heat shock and decreased RNA levels at otherwise pseudouridylated messages, suggesting a role for pseudouridine in enhancing transcript stability. Pseudouridine stoichiometries in rRNA are highly conserved from yeast to mammals, but are reduced in cells derived from dyskeratosis congenita patients, where the pseudouridine synthase DKC1 is mutated, compared to age matched controls. Our results establish pseudouridine as a ubiquitous and dynamic modification in mRNA, and provide a sensitive, quantitative and transcriptome-wide methodology to address its underlying mechanisms and function.
2014-09-11 | GSE60047 | GEO
Project description:We performed pseudouridine profiling (Pseudo-seq) on 11 biological replicates of chromatin-associated RNA. We performed mRNA-seq of PUS1 knockout, PUS7 knockdown, RPUSD4 knockdown and wildtype HepG2 cells. We used an in vitro pool based strategy to assign pre-mRNA targets to individual human pseudouridine synthases (PUS) .
2022-02-15 | GSE123613 | GEO
Project description:In this accession we provide pseudouridylation measurements upon knockdown and/or overexpression three pseudouridine synthases, two of which (TRUB1 and PUS7) we find to be with predominant activity on mammalian mRNA.
2016-12-15 | GSE90851 | GEO
Project description:In an effort to produce a mouse model of Mitochondrial Myopathy with Lactic acidosis and Sideroblastic Anemia (MLASA), we knocked out the gene for Pseudouridine synthase 1 (PUS1), an enzyme that modifies uridine to pseudouridine in many cytoplasmic and mitochondrial tRNAs, as well as other cellular RNAs. The Pus1-/- mice are viable, are born at the expected Mendelian frequency, and are non-dysmorphic. The PUS1 mRNA and certain pseudouridine modifications are absent in cytoplasmic and mitochondrial tRNAs in the Pus1-/- mice. The Pus1-/- mice display reduce exercise capacity at 14 weeks, with alterations in muscle morphology, histology, and physiology. Red gastrocnemius muscle from Pus1-/- mice shows reduced number and size of mitochondria and reduced Cytochrome C oxidase activity. Two-condition, two-color experiment: Mouse wild type PUS1 and homozygous mutant PUS1 kidney tissue samples: 4 biological replicates each.
2016-05-16 | E-GEOD-77819 | biostudies-arrayexpress
Project description:In an effort to produce a mouse model of Mitochondrial Myopathy with Lactic acidosis and Sideroblastic Anemia (MLASA), we knocked out the gene for Pseudouridine synthase 1 (PUS1), an enzyme that modifies uridine to pseudouridine in many cytoplasmic and mitochondrial tRNAs, as well as other cellular RNAs. The Pus1-/- mice are viable, are born at the expected Mendelian frequency, and are non-dysmorphic. The PUS1 mRNA and certain pseudouridine modifications are absent in cytoplasmic and mitochondrial tRNAs in the Pus1-/- mice. The Pus1-/- mice display reduce exercise capacity at 14 weeks, with alterations in muscle morphology, histology, and physiology. Red gastrocnemius muscle from Pus1-/- mice shows reduced number and size of mitochondria and reduced Cytochrome C oxidase activity. Two-condition, two-color experiment: Mouse wild type PUS1 and homozygous mutant PUS1 M1-skeletal muscle (red, slow) tissue samples: 4 biological replicates each.
2016-05-16 | E-GEOD-77821 | biostudies-arrayexpress
Project description:In an effort to produce a mouse model of Mitochondrial Myopathy with Lactic acidosis and Sideroblastic Anemia (MLASA), we knocked out the gene for Pseudouridine synthase 1 (PUS1), an enzyme that modifies uridine to pseudouridine in many cytoplasmic and mitochondrial tRNAs, as well as other cellular RNAs. The Pus1-/- mice are viable, are born at the expected Mendelian frequency, and are non-dysmorphic. The PUS1 mRNA and certain pseudouridine modifications are absent in cytoplasmic and mitochondrial tRNAs in the Pus1-/- mice. The Pus1-/- mice display reduce exercise capacity at 14 weeks, with alterations in muscle morphology, histology, and physiology. Red gastrocnemius muscle from Pus1-/- mice shows reduced number and size of mitochondria and reduced Cytochrome C oxidase activity. Two-condition, two-color experiment: Mouse wild type PUS1 and homozygous mutant PUS1 liver tissue samples: 4 biological replicates each.
2016-05-16 | E-GEOD-77820 | biostudies-arrayexpress