LARP7 suppresses endothelial-to-mesenchymal transition by coupling with TRIM28
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165400 | GEO | 2023/09/22
REPOSITORIES: GEO
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Project description:Valvular heart disease presents a significant health burden, yet advancements in valve biology and novel therapeutics have been hindered by the lack of accessibility to human valve cells. In this study, we have developed a scalable and feeder-free method to differentiate human induced pluripotent stem cells (iPSCs) into endocardial cells. Importantly, we show that these endocardial cells are transcriptionally and phenotypically distinct from vascular endothelial cells and can be directed to undergo endothelial-to-mesenchymal transition (EndMT) to generate cardiac valve cell populations. Following this, we identified two distinct populations—one population undergoes EndMT to become valvular interstitial cells (VICs), while the other population reinforces their endothelial identity to become valvular endothelial cells (VECs). We then characterized our iPSC-derived cell populations and identified putative markers for these populations through bulk RNAseq transcriptome analyses. Lastly, we validated our VIC and VEC populations by comparing our transcriptomic data to pseudobulk data generated from single-cell RNAseq of normal valve tissue from a 15-week-old human fetus. By increasing the accessibility to these cell populations, we aim to accelerate discoveries for cardiac valve biology and disease.
2023-03-03 | GSE226476 | GEO
Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primordial dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.
2020-02-03 | GSE126592 | GEO
Project description:Anti-LARP7 RNA immunoprecipitation (RIP) coupled with RNA-seq assays showed significant enrichment of U6 snRNA, but not other 4 spliceosomal snRNAs, in LARP7 complexes in adult mouse testis.
2019-11-07 | GSE128831 | GEO
Project description:The variations in the protein profile of aortic-valvular (AVE) and endocardial endothelial (EE) cells are currently unknown. The current study's objective is to identify differentially expressed proteins and associated pathways in both endothelial cells. We used endothelial cells isolated from the porcine aortic valve and endocardium for the profiling of proteins. Label-free proteomics was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our proteomics analysis revealed that 29 proteins were highly expressed, and 25 proteins were less represented in the valve than endocardial endothelium. The first part of the study was already available in the ProteomeXchange Consortium (PXD009194).
2022-02-17 | PXD025922 | Pride
Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primordial dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.
2020-02-03 | GSE126682 | GEO
Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primordial dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.
2020-02-03 | GSE126591 | GEO
Project description:We generated genome-wide maps of Pol II and Flag-LARP7 in human HeLa cells. We find that Flag-LARP7 and Pol II co-locolize on Pol II-specific sn/snoRNA genes.
2017-02-02 | GSE87470 | GEO
Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primary dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.
2020-02-03 | GSE134813 | GEO
Project description:Cell senescence is a cell state characterized with permanent cell cycle arrest and elevated proinflammatory secretome and associated with pleiotropic essential physiopathological processes. The persistent DNA damage response (DDR) is the major stress leading to senescence, however the molecular mechanism underling remains elusive. Here, we identified the La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as a novel SIRT1 deacetylase activator. It directly interacted with SIRT1 allosteric regulatory domain and enhanced its deacetylase activity. DDR-mediated ATM activation trigged the extracellular shuttling and downregulation of LARP7 that dampened the SIRT1 deacetylase activity and enhanced p53 and NFB (p65) transcriptional activity by augmenting their acetylation. As a consequence, activated p53 and NFB arrested cell growth and promoted SASP genes expression, and thereby accelerated the cellular senescence. Inducible deletion of LARP7 in wildtype mouse led to senescent cell accumulation and premature ageing. Furthermore, we identified that ATM-LARP7-SIRT1-p53/NFB senescent axis was active in the aortic senescence and atherogenesis. Genetic depletion of LARP7 aggravated the atherogenesis but conversely, inhibited ATM activation or restoring LARP7 expression with genetic manipulation alleviated the vascular aging and atherogenesis. Together, this study identifies LARP7 as a novel SIRT1 cellular activator and it’s-mediated ATM-LARP7-SIRT1-p53/NFB axis is attributed to DDR-mediated cellular senescence and aging-related pathologies.
2021-10-30 | GSE160279 | GEO
Project description:Impaired DNA repair leads to cancer, aging and many genetic diseases. However, understanding of the complexity of DNA is far from complete, resulting in the failure of therapies using genotoxic reagents. Here, we found that LARP7, an RNA-binding protein known to stabilize 7SK RNA, was degraded after DNA injury caused by ionizing radiation and chemotherapy. The LARP7 degradation was catalyzed by an E3 ligase complex of BRCA1 and BARD1 that was triggered by ATM-mediated phosphorylation. LARP7 depletion caused transcriptional repression of the cell cycle regulators CCNB1, CCNB2 and CDK1; this repression arrested cells before the G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation, therefore enhancing Rad51 recruitment and ultimately ensuring the homologous repair of damaged DNA. Importantly, the increased DNA damage repair capacity induced by LARP7 depletion caused resistance to ionizing radiation and CDDP treatment in both wild-type and BRCA1-mutant breast cancer cells and in mouse xenografts. Such resistance also contributed to reduced relapse-free survival rates in breast cancer patients with low levels of LARP7 after chemotherapy. Taken together, the results of this study show that LARP7 coordinates cell cycle progression and faithful DNA repair. We suggest that this mechanism could be exploited to prevent tumorigenesis and improve the effectiveness of cancer therapies.
2019-01-01 | GSE124393 | GEO