LncRNA HOXA-AS2 regulates microglial polarization via recuitment of PRC2 and epigenetic modification of PGC-1α expression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE176167 | GEO | 2021/09/22
REPOSITORIES: GEO
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Project description:BackgroundMicroglia-mediated neuroinflammation plays an important role in Parkinson's disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD.MethodsIn our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization.ResultsWe found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α.ConclusionsOur findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.
| S-EPMC8436538 | biostudies-literature
Project description:LncRNA HOXA-AS2 regulates microglial polarization via recuitment of PRC2 and epigenetic modification of PGC-1α expression
| PRJNA735207 | ENA
Project description:BackgroundNeuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS). PPARγ coactivator-1α (PGC-1α), as a master coregulator of gene expression in mitochondrial biogenesis, was found to be transiently upregulated in microglia after AIS. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown.MethodsPGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Downstream inflammatory cytokine production and NLRP3 activation were also determined. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke.ResultsPGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α.ConclusionsMechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.
| S-EPMC8004413 | biostudies-literature
Project description:Oxidative stress can induce inflammation, promoting macrophage polarization and liver fibrosis following hepatic ischemia-reperfusion (I/R). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has anti-oxidant and anti-inflammatory activity. However, how PGC-1α regulates macrophage polarization following hepatic I/R remains largely unknown. Male C57BL/6 wild-type mice were pre-treated with vehicle or trichostatin A (TSA) for 2 days and subjected to surgical induction of I/R. Liver injury and fibrosis in individual mice were examined longitudinally and the expression levels of IL-6, STAT3, M2-type macrophage markers, Collagen I and α-SMA in the liver of mice were analyzed by immunohistochemistry, RT-qPCR and Western blot. The potential interaction of PGC-1α with phosphorylated NF-kBp65 was determined by immunoprecipitation. The impacts of PGC-1α deficiency in hepatocytes on their IL-6 production and macrophage polarization were tested in a Transwell co-culture system. Moreover, the M2-type macrophage polarization and liver fibrosis were examined in hepatocyte-specific PGC-1α knockout mice and AAV8-mediated PGC-1α over-expressing mice following liver I/R. The down-regulated PGC-1α expression by I/R was negatively correlated with IL-6 levels in the liver of I/R mice and PGC-1α deficiency enhanced IL-6 expression, STAT3 activation and M2-type macrophage polarization in the I/R mice, which were abrogated by TSA treatment. In addition, PGC-1α directly interacted with phosphorylated NF-kBp65 in I/R livers. Hepatocyte-specific PGC-1α deficiency increased IL-6 production and promoted macrophage polarization toward M2 type when co-culture. More importantly, administration with AAV8-PGC-1α rescued the I/R-induced liver fibrosis by inhibiting the IL-6/JAK2/STAT3 signaling and M2-type macrophage polarization in the liver. These results suggest that PGC-1α may alleviate the I/R-induced liver fibrosis by attenuating the IL-6/JAK2/STAT3 signaling to limit M2-type macrophage polarization. PGC-1α may be a therapeutic target for the treatment of liver fibrosis.
| S-EPMC10484946 | biostudies-literature
Project description:Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α play crucial roles in regulating cold-induced thermogenesis in brown adipose tissue (BAT). PGC-1α and NT-PGC-1α are highly induced by cold in BAT and subsequently bind to and coactivate many transcription factors to regulate expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis. To identify the complete repertoire of PGC-1α and NT-PGC-1α target genes in BAT, we analyzed genome-wide DNA-binding and gene expression profiles. We find that PGC-1α-/NT-PGC-1α binding broadly associates with cold-mediated transcriptional activation. In addition to their known target genes in mitochondrial biogenesis and oxidative metabolism, PGC-1α and NT-PGC-1α additionally target a broad spectrum of genes involved in diverse biological pathways including ubiquitin-dependent protein catabolism, ribonucleoprotein complex biosynthesis, phospholipid biosynthesis, angiogenesis, glycogen metabolism, phosphorylation, and autophagy. Our findings expand the number of genes and biological pathways that may be regulated by PGC-1α and NT-PGC-1α and provide further insight into the transcriptional regulatory network in which PGC-1α and NT-PGC-1α coordinate a comprehensive transcriptional response in BAT in response to cold.
| S-EPMC5959870 | biostudies-other
Project description:Emerging evidence have indicated that long non-coding RNAs (lncRNAs) play crucial roles in cancer development and progression. Previous studies have suggested that lncRNA-HOXA cluster antisense RNA 2 (HOXA-AS2) is involved in tumorigenesis of several cancers. However, little is known about the alteration and biological functions of HOXA-AS2 in pancreatic cancer (PC). The purpose of this study is to identify the role of HOXA-AS2 in PC. Here, we provided evidence that lncRNA HOXA-AS2 was up-regulated in PC tissues. In addition, Loss-of-function experiments revealed that HOXA-AS2 knockdown effectively suppressed proliferation by blocking the cell cycle transition and caused apoptosis of PC cells in vitro and in vivo. Mechanistically, we found that HOXA-AS2 directly interacted with enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1), which promoted PC cell growth ability. Collectively, our findings demonstrated that lncRNA-HOXA-AS2/EZH2/LSD1 complex may function as an oncogene in PC cell proliferation, and also provides a potential therapy target for PC.
| S-EPMC5752899 | biostudies-literature
Project description:The expression of lncRNAs in cutaneous squamous cell carcinoma (cSCC) were determined with a commercially available microarray (Arraystar Inc.,Rockville, Maryland USA). The Arraystar human lncRNA Microarray V3.0 containing 30,586 LncRNAs and 26,109 coding transcripts (mRNAs) A total of three patients with cSCC were biopsied. A total of three control (non-lesional skin) were biopsied.
2016-04-13 | E-GEOD-74859 | biostudies-arrayexpress
Project description:As is previously reported, mesenchymal stem cells have potential ability to differentiate into osteocytes. However, the underlying mechanism during this biological process is poorly understood. In the present study, we identify a novel long non-coding RNA named HOXA-AS2 as a critical regulator during the formation of osteogenesis. Attenuation of HOXA-AS2 can reduce the calcium deposition and repress the alkaline phosphatase activity. Moreover, the expressions of osteogenic marker genes are markedly downregulated after HOXA-AS2 depletion. Mechanistically, we found HOXA-AS2 can regulate the transcriptional activity of NF-κB, a critical inhibitor of osteogenesis. More importantly, HOXA-AS2 knockdown could result in the transcriptional repression of the osteogenic master transcription factor SP7 by a NF-κB/HDAC2-coordinated H3K27 deacetylation mechanism. Based on these studies, we conclude that HOXA-AS2 may serve as a promising therapeutic target for bone tissue repair and regeneration in the near future.
| S-EPMC6349193 | biostudies-literature
Project description:BackgroundHOXA cluster antisense RNA2 (HOXA-AS2), a long-chain non-coding RNA, plays an important role in the behavior of various malignant tumors. The roles of HOXA-AS2 in endometrial cancer remain unclear.MethodsWe test expression levels of HOXA-AS2, miRNA-302c-3p, the transcription factor zinc finger X-chromosomal protein (ZFX), and the chitinase-like protein YKL-40 in endometrial carcinoma by qRT-PCR and western blotting. Luciferase reporter and qRT-PCR assays were conducted to identify potential binding sites of HOXA-AS2 to miRNA-302c-3p. Cell cycle, migration and invasion ability of endometrial cancer cells were investigated using flow-cytometric analysis, CCK-8 and transwell assays, respectively.ResultsHOXA-AS2 levels were significantly increased in endometrial cancer specimens compared to normal endometrial specimens. Upregulated HOXA-AS2 promoted invasion and proliferation of type I endometrial cancer cells. HOXA-AS2 silenced miRNA-302c-3p by binding to it. MiRNA-302c-3p negatively regulates ZFX and YKL-40. Thus HOXA-AS2 promotes the development of type I endometrial cancer via miRNA-302c-3p-mediated regulation of ZFX.ConclusionsThese findings suggest that HOXA-AS2 can act as a new therapeutic target for type I endometrial cancer.
| S-EPMC7393821 | biostudies-literature
Project description:Using the highly sensitive lncRNA array, we screened the lncRNAs abundant in the human bladder cancer and Adjacent normal bladder tissues, and the function of differentially expressed lncRNAs were analyzed by bioinformatics. The Arraystar Human lncRNA Array (8x15K, Arraystar) and whole human mRNA Array (4x44K, Arraystar) and was used to profile differentially expressed lncRNAs and genes in bladder cancer vs. normal tissues following the manufacturerâs instructions. Briefly, extracted RNA template (1mg) was reversely transcribed into cDNA and digested into fragments with endonucleases. These fragments were labeled with DNA labeling reagent and labeled cDNAs were hybridized to the microarray via incubation at 45°C and rotated at 60 rpm for 17 h. Following washing and staining, the arrays were scanned using a GeneChip Scanner3000 with GeneChip Operating Software.
2016-07-02 | E-GEOD-83955 | biostudies-arrayexpress