Aging-regulated TUG1 is dispensable for endothelial cell function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA826524 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18746375.fastq.gz | Fastqsanger.gz | |||
| SRR18746376.fastq.gz | Fastqsanger.gz | |||
| SRR18746377.fastq.gz | Fastqsanger.gz | |||
| SRR18746378.fastq.gz | Fastqsanger.gz | |||
| SRR18746379.fastq.gz | Fastqsanger.gz |
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Project description:The evolutionary conserved Taurine Upregulated Gene 1 (TUG1) is a ubiquitously expressed gene that is one of the highest expressed genes in human and rodent endothelial cells (ECs). We here show that TUG1 expression decreases significantly in aging mouse carotid artery ECs and human ECs in vitro, indicating a potential role in the aging endothelial vasculature system. We therefore investigated if, and how, TUG1 might function in aging ECs, but despite extensive phenotyping found no alterations in basal EC proliferation, apoptosis, barrier function, migration, mitochondrial function, or monocyte adhesion upon TUG1 silencing in vitro. TUG1 knockdown did slightly and significantly decrease cumulative sprout length upon vascular endothelial growth factor A stimulation in human umbilical vein endothelial cells (HUVECs), though TUG1-silenced HUVECs displayed no transcriptome-wide mRNA expression changes explaining this effect. Further, ectopic expression of the highly conserved and recently discovered 153 amino acid protein translated from certain TUG1 transcript isoforms did not alter angiogenic sprouting in vitro. Our data show that, despite a high expression and strong evolutionary conservation of both the TUG1 locus and the protein sequence it encodes, TUG1 does not seem to play a major role in basic endothelial cell function.
2022-07-20 | GSE200766 | GEO
Project description:The evolutionary conserved Taurine Upregulated Gene 1 (TUG1) is a ubiquitously expressed gene that is one of the highest expressed genes in human and rodent endothelial cells (ECs). We here show that TUG1 expression decreases significantly in aging mouse carotid artery ECs and human ECs in vitro, indicating a potential role in the aging endothelial vasculature system. We therefore investigated if, and how, TUG1 might function in aging ECs, but despite extensive phenotyping found no alterations in basal EC proliferation, apoptosis, barrier function, migration, mitochondrial function, or monocyte adhesion upon TUG1 silencing in vitro. TUG1 knockdown did slightly and significantly decrease cumulative sprout length upon vascular endothelial growth factor A stimulation in human umbilical vein endothelial cells (HUVECs), though TUG1-silenced HUVECs displayed no transcriptome-wide mRNA expression changes explaining this effect. Further, ectopic expression of the highly conserved and recently discovered 153 amino acid protein translated from certain TUG1 transcript isoforms did not alter angiogenic sprouting in vitro. Our data show that, despite a high expression and strong evolutionary conservation of both the TUG1 locus and the protein sequence it encodes, TUG1 does not seem to play a major role in basic endothelial cell function.
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Project description:Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression
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Project description:Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression [PNUTS]
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Project description:Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determined the role of PNUTS in endothelial cell aging. We confirmed that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. To validate our findings in vivo, we generated an endothelial-specific inducible PNUTS-deficient mouse line (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice presented severe multiorgan failure and vascular leakage. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice revealed that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restored barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs.
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Project description:We have sequenced mouse embryonic fibroblasts (MEFs) and 6 organs (testes, prostate, liver, heart, spleen, and eye) harvested from adult male wild type and Tug1 knockout (Tug1_tm1.1Vlcg) mice in a C57BL/6J/129S6 (N3-C57BL/6J, no Neo) background. Additional sequencing was done on the testes of a Tug1 rescue mouse, which contains a doxycycline inducible allele for Tug1 (tg(Tug1)) and CAGs-rtTA3 in the Tug1 knockout background (Tug1_tmn1.1Vlcg).
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Project description:Cardiomyocyte Ca2+ is buffered by mitochondria via the mitochondrial calcium uniporter (MCU) complex. The MCU complex consists of pore-forming proteins including the mitochondrial calcium uniporter (MCU), and regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 affected the expression of MCU-associated genes. To further explore this, we knocked down Tug1 (Tug1 KD) in H9c2 rat cardiomyocytes using antisense LNA oligo. This led to increased MCU protein expression yet this did not enhance a marker of mitochondrial Ca2+ uptake. RNA-seq revealed that Tug1 KD increased Mcu and led to differential expression of genes and pathways related to Ca2+ regulation in the heart. To understand the effect of this on Ca2+ signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to promote Mcu gene expression. Tug1 KD attenuated the increase in CAMKII and CREB phosphorylation in response to ionomycin, a Ca2+ ionophore. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD mediated increase in Mcu. Together, these data suggest that Tug1 modulates MCU expression via a mechanism that may involve CAMKII and CREB. The Tug1 mediated regulation of MCU on mitochondrial Ca2+ uptake, may have functional consequences for cellular Ca2+ handling which could have implications for cardiac disease.
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