Pseudouridylation of 7SK by PUS7 regulates Pol II transcription elongation
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PROVIDER: PRJNA1216229 | ENA |
REPOSITORIES: ENA
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Project description:Pseudouridine (Ψ) is a widespread RNA modification in various RNA species, including rRNA, tRNA, snRNA and mRNA. Ψ plays a crucial role in RNA metabolism, where it regulates pre-mRNA splicing and affects protein translation. Whether and how Ψ may regulate transcription have not be adequately studied. Here, we report that pseudorudine synthase 7 (PUS7) can mediate pseudouridylation of 7SK small nuclear RNA (snRNA), a regulator of RNA polymerase II (Pol II) promoter-proximal pausing. PUS7 loss leads to hypo-pseudouridylation and facilitates sequestration of the positive transcription elongation factor b (P-TEFb) complex from 7SK. The release of P-TEFb from 7SK increases serine 2 phosphorylation (Ser2P) in the RNA Pol II C-terminal domain and enhances transcription elongation. In colorectal cancer (CRC) cells, the Ψ level of 7SK could be modulated by PUS7, or by site-specifically targeted pseudouridylation through dCas13b-guided system. Hypo-pseudouridylation on 7SK with PUS7 depletion promotes KLF6/DDIT3-mediated cell apoptosis and sensitizes CRC cells to 5-FU.
2025-09-09 | GSE288120 | GEO
Project description: Not available
| S-EPMC12575831 | biostudies-literature
Project description:Human PUS7 in tRNA pseudouridylation
| PRJNA613911 | ENA
Project description:Background: Pulmonary hypertension (PH) is a life-threatening cardiovascular disorder characterized by irreversible pulmonary vascular remodeling and poor prognosis. RNA pseudouridylation, the most evolutionarily conserved RNA epigenetic modification, and its catalytic enzyme pseudouridine synthase 7 (PUS7) remained uncharacterized in PH, representing a major gap in understanding the epigenetic pathogenesis of the disease. Methods: We generated the first single-base resolution pseudouridine (Ψ) landscape in lung tissues of PH patients using bisulfite-induced deletion sequencing (BID-seq). PUS7 expression was analyzed in hypoxic pulmonary artery endothelial cells (PAECs), the lung tissues of PH patients, and Su5416-hypoxia rodent model. The functional roles of PUS7 were investigated through genetic manipulation (PUS7-deficiency cells, AAV-mediated overexpression, endothelial cell-specific knockdown, and heterozygous knockout mice) and pharmacological inhibition using NSC107512. Results: BID-seq revealed global Ψ dysregulation in the PH patient lung tissues. Among PUS family members, PUS7 was the most markedly upregulated in these tissues and in the hypoxic PAECs. Both gene knockdown and pharmacological inhibition with NSC107512 ameliorated PH, whereas AAV-mediated PUS7 overexpression exacerbated disease progression. RNA immunoprecipitation sequencing and mutagenesis studies demonstrated that PUS7 bound to and catalyzed Ψ at position 688 of Transforming Growth Factor Beta Induced Protein (TGFBI) mRNA, thereby stabilizing TGFBI and activating Phosphatidylinositol 3 Kinase (PI3K)-Protein Kinase B (AKT) signaling pathway. Furthermore, hypoxia-inducible factor 2α (HIF-2α) directly bound the PUS7 promoter, estabilishing a HIF-2α/PUS7/TGFBI/PI3K-AKT positive feedback loop that drives PH pathogenesis. Conclusions: PUS7-mediated pseudouridylation serves as a novel epigenetic driver of PH via the HIF-2α/PUS7/TGFBI/PI3K-AKT axis, positioning PUS7 as a promising therapeutic target for this devastating disease.
2026-07-07 | GSE334990 | GEO
Project description:Background: Pulmonary hypertension (PH) is a life-threatening cardiovascular disorder characterized by irreversible pulmonary vascular remodeling and poor prognosis. RNA pseudouridylation, the most evolutionarily conserved RNA epigenetic modification, and its catalytic enzyme pseudouridine synthase 7 (PUS7) remained uncharacterized in PH, representing a major gap in understanding the epigenetic pathogenesis of the disease. Methods: We generated the first single-base resolution pseudouridine (Ψ) landscape in lung tissues of PH patients using bisulfite-induced deletion sequencing (BID-seq). PUS7 expression was analyzed in hypoxic pulmonary artery endothelial cells (PAECs), the lung tissues of PH patients, and Su5416-hypoxia rodent model. The functional roles of PUS7 were investigated through genetic manipulation (PUS7-deficiency cells, AAV-mediated overexpression, endothelial cell-specific knockdown, and heterozygous knockout mice) and pharmacological inhibition using NSC107512. Results: BID-seq revealed global Ψ dysregulation in the PH patient lung tissues. Among PUS family members, PUS7 was the most markedly upregulated in these tissues and in the hypoxic PAECs. Both gene knockdown and pharmacological inhibition with NSC107512 ameliorated PH, whereas AAV-mediated PUS7 overexpression exacerbated disease progression. RNA immunoprecipitation sequencing and mutagenesis studies demonstrated that PUS7 bound to and catalyzed Ψ at position 688 of Transforming Growth Factor Beta Induced Protein (TGFBI) mRNA, thereby stabilizing TGFBI and activating Phosphatidylinositol 3 Kinase (PI3K)-Protein Kinase B (AKT) signaling pathway. Furthermore, hypoxia-inducible factor 2α (HIF-2α) directly bound the PUS7 promoter, estabilishing a HIF-2α/PUS7/TGFBI/PI3K-AKT positive feedback loop that drives PH pathogenesis. Conclusions: PUS7-mediated pseudouridylation serves as a novel epigenetic driver of PH via the HIF-2α/PUS7/TGFBI/PI3K-AKT axis, positioning PUS7 as a promising therapeutic target for this devastating disease.
2026-07-07 | GSE334780 | GEO
Project description:Background: Pulmonary hypertension (PH) is a life-threatening cardiovascular disorder characterized by irreversible pulmonary vascular remodeling and poor prognosis. RNA pseudouridylation, the most evolutionarily conserved RNA epigenetic modification, and its catalytic enzyme pseudouridine synthase 7 (PUS7) remained uncharacterized in PH, representing a major gap in understanding the epigenetic pathogenesis of the disease. Methods: We generated the first single-base resolution pseudouridine (Ψ) landscape in lung tissues of PH patients using bisulfite-induced deletion sequencing (BID-seq). PUS7 expression was analyzed in hypoxic pulmonary artery endothelial cells (PAECs), the lung tissues of PH patients, and Su5416-hypoxia rodent model. The functional roles of PUS7 were investigated through genetic manipulation (PUS7-deficiency cells, AAV-mediated overexpression, endothelial cell-specific knockdown, and heterozygous knockout mice) and pharmacological inhibition using NSC107512. Results: BID-seq revealed global Ψ dysregulation in the PH patient lung tissues. Among PUS family members, PUS7 was the most markedly upregulated in these tissues and in the hypoxic PAECs. Both gene knockdown and pharmacological inhibition with NSC107512 ameliorated PH, whereas AAV-mediated PUS7 overexpression exacerbated disease progression. RNA immunoprecipitation sequencing and mutagenesis studies demonstrated that PUS7 bound to and catalyzed Ψ at position 688 of Transforming Growth Factor Beta Induced Protein (TGFBI) mRNA, thereby stabilizing TGFBI and activating Phosphatidylinositol 3 Kinase (PI3K)-Protein Kinase B (AKT) signaling pathway. Furthermore, hypoxia-inducible factor 2α (HIF-2α) directly bound the PUS7 promoter, estabilishing a HIF-2α/PUS7/TGFBI/PI3K-AKT positive feedback loop that drives PH pathogenesis. Conclusions: PUS7-mediated pseudouridylation serves as a novel epigenetic driver of PH via the HIF-2α/PUS7/TGFBI/PI3K-AKT axis, positioning PUS7 as a promising therapeutic target for this devastating disease.
2026-07-07 | GSE335228 | GEO
Project description:Background: Pulmonary hypertension (PH) is a life-threatening cardiovascular disorder characterized by irreversible pulmonary vascular remodeling and poor prognosis. RNA pseudouridylation, the most evolutionarily conserved RNA epigenetic modification, and its catalytic enzyme pseudouridine synthase 7 (PUS7) remained uncharacterized in PH, representing a major gap in understanding the epigenetic pathogenesis of the disease. Methods: We generated the first single-base resolution pseudouridine (Ψ) landscape in lung tissues of PH patients using bisulfite-induced deletion sequencing (BID-seq). PUS7 expression was analyzed in hypoxic pulmonary artery endothelial cells (PAECs), the lung tissues of PH patients, and Su5416-hypoxia rodent model. The functional roles of PUS7 were investigated through genetic manipulation (PUS7-deficiency cells, AAV-mediated overexpression, endothelial cell-specific knockdown, and heterozygous knockout mice) and pharmacological inhibition using NSC107512. Results: BID-seq revealed global Ψ dysregulation in the PH patient lung tissues. Among PUS family members, PUS7 was the most markedly upregulated in these tissues and in the hypoxic PAECs. Both gene knockdown and pharmacological inhibition with NSC107512 ameliorated PH, whereas AAV-mediated PUS7 overexpression exacerbated disease progression. RNA immunoprecipitation sequencing and mutagenesis studies demonstrated that PUS7 bound to and catalyzed Ψ at position 688 of Transforming Growth Factor Beta Induced Protein (TGFBI) mRNA, thereby stabilizing TGFBI and activating Phosphatidylinositol 3 Kinase (PI3K)-Protein Kinase B (AKT) signaling pathway. Furthermore, hypoxia-inducible factor 2α (HIF-2α) directly bound the PUS7 promoter, estabilishing a HIF-2α/PUS7/TGFBI/PI3K-AKT positive feedback loop that drives PH pathogenesis. Conclusions: PUS7-mediated pseudouridylation serves as a novel epigenetic driver of PH via the HIF-2α/PUS7/TGFBI/PI3K-AKT axis, positioning PUS7 as a promising therapeutic target for this devastating disease.
2026-07-07 | GSE335339 | 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:The transition from transcription initiation into elongation at promoters of primary response genes (PRG) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA Polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoters in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP). However, it remains unclear how and why the 7SK snRNP is assembled at promoters. Here we report that the transcriptional regulator KAP1 directly recruits the 7SK snRNP to facilitate localized release of P-TEFb, promoting rapid Pol II elongation and PRG synthesis in response to stimuli. Collectively, we have discovered and characterized a novel complex, which we term the KEC, which dictates rapid and robust PRG induction upon stimuli.
2015-10-09 | GSE72622 | GEO
Project description:We describe six patients from three families with three homozygous protein truncating variants in PUS7: c.89_90del, p.(Thr30Lysfs20*); c.1348C>T, p.(Arg450*); and a deletion of the penultimate exon 15. All patients have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, Pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity with slower walking speed and disorientation supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.
2018-10-13 | GSE121177 | GEO