Dataset Information

Reduction of GAS5 and FOXD3-AS1 long non-coding RNAs in patients with bipolar disorder.

ABSTRACT: Bipolar disorder (BD) patients suffer from severe disability and premature death because of failure in prognosis, diagnosis, and treatment. Although neural mechanisms of bipolar have not been fully discovered, studies have shown long noncoding RNAs (lncRNAs) can play an important role in signaling pathways such as PI3K/AKT pathway. There has been little study on deregulated lncRNAs and the lncRNAs' mode of action in the BD. Hence, we aimed to investigate the expression of PI3K/AKT pathway-related lncRNAs named TUG1, GAS5, and FOXD3-AS1 lncRNAs in the PMBC in 50 bipolar patients and 50 healthy controls. Our results showed that FOXD3-AS1 and GAS5 under-expressed significantly in bipolar patients compared to healthy controls (P = 0.0028 and P < 0.0001 respectively). Moreover, after adjustment, all P values remained significant (q value < 0.0001). According to the ROC curve, AUC (area under the curve), specificity, and sensitivity of these lncRNAs, GAS5 and FOXD3-AS1 might work as BD candidate diagnostic biomarkers. Taken together, the current results highlight that the dysregulation of FOXD3-AS1 and GAS5 may be associated with an increased risk of BD.

SUBMITTER: Zamani B

PROVIDER: S-EPMC10449891 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Reduction of GAS5 and FOXD3-AS1 long non-coding RNAs in patients with bipolar disorder.

Zamani Bita B Mehrab Mohseni Mahdieh M Naghavi Gargari Bahar B Taheri Mohammad M Sayad Arezou A Shirvani-Farsani Zeinab Z

Scientific reports 20230824 1

Bipolar disorder (BD) patients suffer from severe disability and premature death because of failure in prognosis, diagnosis, and treatment. Although neural mechanisms of bipolar have not been fully discovered, studies have shown long noncoding RNAs (lncRNAs) can play an important role in signaling pathways such as PI3K/AKT pathway. There has been little study on deregulated lncRNAs and the lncRNAs' mode of action in the BD. Hence, we aimed to investigate the expression of PI3K/AKT pathway-relate ...[more]

PMID: 37620425

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Project description:Macrophages (Mφ) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of Mφ will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of Mφ polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to Mφ differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and in vitro differentiated M2 Mφ identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs viz., RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 Mφ and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 Mφ. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 Mφ transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled E. coli in vitro by M1/M2 Mφ, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.

Project description:BackgroundMalignant pleural mesothelioma (MPM) is an aggressive cancer with short overall survival. Long non-coding RNAs (lncRNA) are a class of RNAs more than 200 nucleotides long that do not code for protein and are part of the 90% of the human genome that is transcribed. Earlier experimental studies in mice showed GAS5 (growth arrest specific transcript 5) gene deletion in asbestos driven mesothelioma. GAS5 encodes for a lncRNA whose function is not well known, but it has been shown to act as glucocorticoid receptor decoy and microRNA "sponge". Our aim was to investigate the possible role of the GAS5 in the growth of MPM.MethodsPrimary MPM cultures grown in serum-free condition in 3% oxygen or MPM cell lines grown in serum-containing medium were used to investigate the modulation of GAS5 by growth arrest after inhibition of Hedgehog or PI3K/mTOR signalling. Cell cycle length was determined by EdU incorporation assay in doxycycline inducible short hairpinGAS5 clones generated from ZL55SPT cells. Gene expression was quantified by quantitative PCR. To investigate the GAS5 promoter, a 0.77 kb sequence was inserted into a pGL3 reporter vector and luciferase activity was determined after transfection into MPM cells. Localization of GAS5 lncRNA was identified by in situ hybridization. To characterize cells expressing GAS5, expression of podoplanin and Ki-67 was assessed by immunohistochemistry.ResultsGAS5 expression was lower in MPM cell lines compared to normal mesothelial cells. GAS5 was upregulated upon growth arrest induced by inhibition of Hedgehog and PI3K/mTOR signalling in in vitro MPM models. The increase in GAS5 lncRNA was accompanied by increased promoter activity. Silencing of GAS5 increased the expression of glucocorticoid responsive genes glucocorticoid inducible leucine-zipper and serum/glucocorticoid-regulated kinase-1 and shortened the length of the cell cycle. Drug induced growth arrest was associated with GAS5 accumulation in the nuclei. GAS5 was abundant in tumoral quiescent cells and it was correlated to podoplanin expression.ConclusionsThe observations that GAS5 levels modify cell proliferation in vitro, and that GAS5 expression in MPM tissue is associated with cell quiescence and podoplanin expression support a role of GAS5 in MPM biology.

Dataset Information

Reduction of GAS5 and FOXD3-AS1 long non-coding RNAs in patients with bipolar disorder.

Publications

Reduction of GAS5 and FOXD3-AS1 long non-coding RNAs in patients with bipolar disorder.

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