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  • Uddin, Monica  (3)
  • 2020-2024  (3)
  • 1
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    Online Resource
    Increased H3K4me3 methylation and decreased miR-7113-5p expression lead to enhanced Wnt/β-catenin signaling in immune cells from PTSD patients leading to inflammatory phenotype
    Springer Science and Business Media LLC ; 2020
    In:  Molecular Medicine Vol. 26, No. 1 ( 2020-12)
    Details
    In: Molecular Medicine, Springer Science and Business Media LLC, Vol. 26, No. 1 ( 2020-12)
    Abstract: Posttraumatic stress disorder (PTSD) is a psychiatric disorder accompanied by chronic peripheral inflammation. What triggers inflammation in PTSD is currently unclear. In the present study, we identified potential defects in signaling pathways in peripheral blood mononuclear cells (PBMCs) from individuals with PTSD. Methods RNAseq (5 samples each for controls and PTSD), ChIPseq (5 samples each) and miRNA array (6 samples each) were used in combination with bioinformatics tools to identify dysregulated genes in PBMCs. Real time qRT-PCR (24 samples each) and in vitro assays were employed to validate our primary findings and hypothesis. Results By RNA-seq analysis of PBMCs, we found that Wnt signaling pathway was upregulated in PTSD when compared to normal controls. Specifically, we found increased expression of WNT10B in the PTSD group when compared to controls. Our findings were confirmed using NCBI’s GEO database involving a larger sample size. Additionally, in vitro activation studies revealed that activated but not naïve PBMCs from control individuals expressed more IFN γ in the presence of recombinant WNT10B suggesting that Wnt signaling played a crucial role in exacerbating inflammation. Next, we investigated the mechanism of induction of WNT10B and found that increased expression of WNT10B may result from epigenetic modulation involving downregulation of hsa-miR-7113-5p which targeted WNT10B . Furthermore, we also observed that WNT10B overexpression was linked to higher expression of H3K4me3 histone modification around the promotor of WNT10B . Additionally, knockdown of histone demethylase specific to H3K4me3, using siRNA, led to increased expression of WNT10B providing conclusive evidence that H3K4me3 indeed controlled WNT10B expression. Conclusions In summary, our data demonstrate for the first time that Wnt signaling pathway is upregulated in PBMCs of PTSD patients resulting from epigenetic changes involving microRNA dysregulation and histone modifications, which in turn may promote the inflammatory phenotype in such cells.
    Type of Medium: Online Resource
    ISSN: 1076-1551 , 1528-3658
    URL: Article
    DOI: 10.1186/s10020-020-00238-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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    detail.hit.zdb_id: 1283676-X
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  • 2
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    Dysregulated TP53 Among PTSD Patients Leads to Downregulation of miRNA let-7a and Promotes an Inflammatory Th17 Phenotype
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 12 ( 2022-1-4)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2022-1-4)
    Abstract: Post-traumatic stress disorder (PTSD) is a psychiatric disorder and patients diagnosed with PTSD often express other comorbid health issues, particularly autoimmune and inflammatory disorders. Our previous reports investigating peripheral blood mononuclear cells (PBMCs) from PTSD patients showed that these patients exhibit an increased inflammatory T helper (Th) cell phenotype and widespread downregulation of microRNAs (miRNAs), key molecules involved in post-transcriptional gene regulation. A combination of analyzing prior datasets on gene and miRNA expression of PBMCs from PTSD and Control samples, as well as experiments using primary PBMCs collected from human PTSD and Controls blood, was used to evaluate TP53 expression, DNA methylation, and miRNA modulation on Th17 development. In the current report, we note several downregulated miRNAs were linked to tumor protein 53 (TP53), also known as p53. Expression data from PBMCs revealed that compared to Controls, PTSD patients exhibited decreased TP53 which correlated with an increased inflammatory Th17 phenotype. Decreased expression of TP53 in the PTSD population was shown to be associated with an increase in DNA methylation in the TP53 promotor region. Lastly, the most significantly downregulated TP53-associated miRNA, let-7a, was shown to negatively regulate Th17 T cells. Let-7a modulation in activated CD4+ T cells was shown to influence Th17 development and function, via alterations in IL-6 and IL-17 production, respectively. Collectively, these studies reveal that PTSD patients could be susceptible to inflammation by epigenetic dysregulation of TP53, which alters the miRNA profile to favor a proinflammatory Th17 phenotype.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2021.815840
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 3
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    Long non-coding RNA LINC00926 regulates WNT10B signaling pathway thereby altering inflammatory gene expression in PTSD
    Springer Science and Business Media LLC ; 2022
    In:  Translational Psychiatry Vol. 12, No. 1 ( 2022-05-12)
    Details
    In: Translational Psychiatry, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-05-12)
    Abstract: Post-traumatic stress disorder (PTSD), which frequently occurs in the aftermath of a psychologically traumatic event is characterized by heightened inflammation. People with PTSD also suffer from a number of comorbid clinical and behavioral disorders that are related to chronic inflammation. Thus, understanding the mechanisms of enhanced inflammation in PTSD can provide insights into the relationship between PTSD and associated comorbid disorders. In the current study, we investigated the role of large intervening non-coding RNAs (lincRNAs) in the regulation of inflammation in people diagnosed with PTSD. We observed that WNT ligand, WNT10B, was upregulated in the peripheral blood mononuclear cells (PBMCs) of PTSD patients. This observation was associated with higher H3K4me3 signals around WNT10B promotor in PTSD patients compared to those without PTSD. Increased H3K4me3 resulted from LINC00926, which we found to be upregulated in the PTSD sample, bringing in histone methyltransferase, MLL1, onto WNT10B promotor leading to the introduction of H3K4 trimethylation. The addition of recombinant human WNT10B to pre-activated peripheral blood mononuclear cells (PBMCs) led to increased expression of inflammatory genes such as IFNG and IL17A, suggesting that WNT10B is involved in their upregulation. Together, our data suggested that LINC00926 interacts physically with MLL1 and thereby controls the expression of IFNG and IL17A. This is the first time a long non-coding RNA is shown to regulate the expression of WNT10B and consequently inflammation. This observation has high relevance to our understanding of disease mechanisms of PTSD and comorbidities associated with PTSD.
    Type of Medium: Online Resource
    ISSN: 2158-3188
    URL: Article
    DOI: 10.1038/s41398-022-01971-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2609311-X
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