Esrrg inhibition protects against PM2.5-induced asthma aggravation by reducing Pde3b
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ABSTRACT:
PROVIDER: PRJNA1207686 | ENA |
REPOSITORIES: ENA
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Project description:PM2.5 exposure is closely linked to the exacerbation of asthma. Estrogen related receptor gamma (Esrrg), an orphan nuclear receptor, exerts a crucial role as a transcription factor in various metabolic diseases. Nevertheless, the impacts of Esrrg on PM2.5-triggered asthma aggravation have not been investigated. Herein, ovalbumin (OVA)-induced asthmatic mice were exposed to PM2.5 to establish a mouse model of asthma aggravation by PM2.5. In view of mRNA sequencing, Esrrg was the only member of nuclear receptor superfamily in the up-regulated differentially expressed genes in OVA compared with Naive groups as well as OVA+PM2.5 compared with OVA groups (|log2 (fold change)|>1 and p<0.05). In vivo, adeno-associated virus carrying Esrrg shRNA (AAV-shEsrrg) was applied to silencing Esrrg. In addition, Esrrg activity was suppressed pharmacologically with an inverse agonist GSK5182. Either AAV-shEsrrg or GSK5182 ameliorated airway inflammation in the PM2.5-aggravated asthmatic mice. In vitro, isolated mouse primary tracheobronchial epithelial cells (MTEC) from mice were identified by detecting cytokeratin 7-positive cells. The treatment of adenovirus vector with shEsrrg or GSK5182 mitigated the cell damage induced by PM2.5. Notably, phosphodiesterase 3B (Pde3b) expression was declined by Esrrg inhibition in vivo and in vitro. Dual luciferase reporter and ChIP-PCR assays showed the binding of Esrrg to the Pde3b promoter. Taken together, these results revealed that Esrrg inhibition alleviated airway inflammation in the PM2.5-deteriorated asthmatic mouse model and prevented PM2.5-driven MTEC injury through binding to the Pde3b promoter, which might contribute to further study the therapy of PM2.5-aggravated asthma.
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Project description:Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 16 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify novel Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death which is exacerbated in hypoxia. These findings reveal a novel dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.
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Project description:To investigate insight into how Esrrg regulates the TREG transcriptional program, we performed high-throughput RNA sequencing (RNA-seq) analysis of CD4+Foxp3-YFP+ from splenic cells of WT and KO female mice (2-3 months old). We show that the Esrrg-deficient Treg cells presented increased transcript related to oxidative phosphoration, cell cycle, proteasome, and antigen-presenting, suggesting Esrrg plays an essential role in mitochondral metabolism and it is associated with antigen-presenting and processing. Finally, Esrrg-deficient Treg displayed decreased Erbb and ribosome pathway, which may also related to TREG function. Our data suggest an critical role of lupus susceptibility gene Esrrg in regulating Treg cell function through mitochondrial metabolism.
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Project description:Purpose: The goal of this study is to understand what gene changes are associated with removal of Esrrg in dopaminerigc neurons from the mouse midbrain using BAC-TRAP and an AAV for Thcre Methods: Midbrain from mice expressing the L10a transgene used for BAC-TRAP method of RNA isolation both with and without deletion of Esrrg using AAV:THCre were aged 1 month post-injection and midbrains were then extracted and flash frozen on dry ice. RNA was isolated using the BAC-TRAP method and samples were sent for sequencing.
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