The Long Non-Coding Antisense RNA JHDM1D-AS1 Regulates Inflammatory Responses in Human Monocytes

Malmström, Erik; Khan, Hina; Veer, Cornelis van ’t; Stunnenberg, Melissa; Meijer, Mariska T.; Matsumoto, Hisatake; Otto, Natasja A.; Geijtenbeek, Teunis B. H.; Vos, Alex F. de; Poll, Tom van der; Scicluna, Brendon P.

doi:10.3389/fcimb.2022.934313

Cited by 6 publications

(5 citation statements)

References 44 publications

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“…In a recent study, experiments of overexpression and knockdown of KDM7A-DT in monocytes imply that this lncRNA influences cell development and homeostasis pathways. Furthermore, the above research proposes that KDM7A-DT acts as an inflammatory response regulator, which aligns with our findings ( 70 ). It is well known that stressed cells first activate the DDR/R pathway to perform DNA damage assessment, then enter the S-phase and initiate mitosis, arrest, or apoptosis.…”

Section: Discussionsupporting

confidence: 92%

“…The molecular signature across breast cancer subtypes does not appear to represent distinct states but rather transitional ones, capable of inter-conversion due to intratumor clonal and cell-state heterogeneity. Clonal heterogeneity is defined by a multi-level selection process of cloned populations within a tumor based on their phenotypic variance, which is affected by both spatial and temporal factors ( 70 ). Clonal evolution of a dominant or resistant clone is a potential mechanism for malignant spread and treatment resistance.…”

Section: Discussionmentioning

confidence: 99%

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KDM7A-DT induces genotoxic stress, tumorigenesis, and progression of p53 missense mutation-associated invasive breast cancer

Giannakakis,

Tsifintaris,

Gouzouasis

et al. 2024

Front. Oncol.

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Stress-induced promoter-associated and antisense lncRNAs (si-paancRNAs) originate from a reservoir of oxidative stress (OS)-specific promoters via RNAPII pausing-mediated divergent antisense transcription. Several studies have shown that the KDM7A divergent transcript gene (KDM7A-DT), which encodes a si-paancRNA, is overexpressed in some cancer types. However, the mechanisms of this overexpression and its corresponding roles in oncogenesis and cancer progression are poorly understood. We found that KDM7A-DT expression is correlated with highly aggressive cancer types and specific inherently determined subtypes (such as ductal invasive breast carcinoma (BRCA) basal subtype). Its regulation is determined by missense TP53 mutations in a subtype-specific context. KDM7A-DT transcribes several intermediate-sized ncRNAs and a full-length transcript, exhibiting distinct expression and localization patterns. Overexpression of KDM7A-DT upregulates TP53 protein expression and H2AX phosphorylation in nonmalignant fibroblasts, while in semi-transformed fibroblasts, OS superinduces KDM7A-DT expression in a TP53-dependent manner. KDM7A-DT knockdown and gene expression profiling in TP53-missense mutated luminal A BRCA variant, where it is abundantly expressed, indicate its significant role in cancer pathways. Endogenous over-expression of KDM7A-DT inhibits DNA damage response/repair (DDR/R) via the TP53BP1-mediated pathway, reducing apoptosis and promoting G2/M checkpoint arrest. Higher KDM7A-DT expression in BRCA is associated with KDM7A-DT locus gain/amplification, higher histologic grade, aneuploidy, hypoxia, immune modulation scores, and activation of the c-myc pathway. Higher KDM7A-DT expression is associated with relatively poor survival outcomes in patients with luminal A or Basal subtypes. In contrast, it is associated with favorable outcomes in patients with HER2+ER- or luminal B subtypes. KDM7A-DT levels are coregulated with critical transcripts and proteins aberrantly expressed in BRCA, including those involved in DNA repair via non-homologous end joining and epithelial-to-mesenchymal transition pathway. In summary, KDM7A-DT and its si-lncRNA exhibit several intrinsic biological and clinical characteristics that suggest important roles in invasive BRCA and its subtypes. KDM7A-DT-defined mRNA and protein subnetworks offer resources for identifying clinically relevant RNA-based signatures and prospective targets for therapeutic intervention.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

KDM7A-DT induces genotoxic stress, tumorigenesis, and progression of p53 missense mutation-associated invasive breast cancer

Giannakakis,

Tsifintaris,

Gouzouasis

et al. 2024

Front. Oncol.

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“…We found higher levels of IL-1β , C3AR1 , and IL1R1 transcripts in patients with sepsis ( Fig 6F–6H ) and a positive correlation between expression levels of IL-1β and C3AR1 in sepsis patients but not healthy controls ( Fig 6I and 6J ). Finally, we analyzed whole-blood transcriptional data from a cohort that included patients admitted to the intensive care unit (ICU) with sepsis, patients admitted to the ICU with non-infectious conditions, and healthy controls [ 25 ]. We found positive correlation between expression of IL-1β and C3AR1 only in patients suffering from sepsis ( Fig 6K–6M ).…”

Section: Resultsmentioning

confidence: 99%

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β

Zigdon,

Sawaed,

Zelik

et al. 2024

PLoS Biol

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Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. Mice lacking IL-1β (IL-1β -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1β -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss prevented mortality in Salmonella-infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

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“…For example, lncRNA MEG3 is overexpressed in sepsis, which is associated with increased disease risk, systemic in ammation, disease severity, and poor prognosis in sepsis patients [23] . lncRNA JHDM1D-AS1 is up-regulated in patients with sepsis, which induces TLR activation and inhibits monocyte/macrophage in ammatory response [24] . Down-regulation of lncRNA CRNDE can reduce kidney injury caused by sepsis by inhibiting the TLR3/NF-κB pathway [25] .…”

Section: Discussionmentioning

confidence: 99%

Identification of immune-related lncRNAs in peripheral blood of sepsis by transcriptome sequencing and analysis core lncRNA PRKCQ-AS1 roles in prognosis and progression of sepsis

Ding

Liang

Xia

et al. 2023

Preprint

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Sepsis is a high mortality and great harm systemic inflammatory response syndrome caused by infection. lncRNAs are potential prognostic marker and therapeutic target. Therefore, we expect to screen and analyze lncRNAs with potential prognostic markers in sepsis. We obtained 2310 differentially expressed (DE) lncRNAs and 7310 DEmRNAs by transcriptome sequencing. Then the immune-related lncRNA-mRNA regulatory network, which contains 14 core lncRNAs, was constructed by functional enrichment and Pearson correlation analysis. The results of immune infiltration, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) further confirmed the correlation between 14 key lncRNAs and immune cells. Subsequently, the key immune-related lncRNA PRKCQ-AS1 was identified by weighted gene co-expression network analysis (WGCNA). RT-qPCR showed that PRKCQ-AS1 was up-regulated in clinical samples and sepsis model cells (LPS-induced HUVECs). Kaplan-Meier (KM), receiver operator characteristic (ROC), Cox regression analysis and nomogram confirmed that PRKCQ-AS1 was an independent prognostic factor in sepsis patients. Immune correlation analysis showed that PRKCQ-AS1 was involved in the immune response and inflammatory process of sepsis. Cell function assay confirmed that PRKCQ-AS1 could inhibit the LPS-induced sepsis model cells viability and promote cell apoptosis, inflammatory damage and oxidative stress. In conclusion, we constructed immune-related lncRNA-mRNA regulatory networks in the progression of sepsis and analyzed the role of PRKCQ-AS1 in the prognosis and progression of sepsis. It is confirmed that PRKCQ-AS1 is an important prognostic factor affecting the progression of sepsis and is involved in immune response.

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The Long Non-Coding Antisense RNA JHDM1D-AS1 Regulates Inflammatory Responses in Human Monocytes

Cited by 6 publications

References 44 publications

KDM7A-DT induces genotoxic stress, tumorigenesis, and progression of p53 missense mutation-associated invasive breast cancer

KDM7A-DT induces genotoxic stress, tumorigenesis, and progression of p53 missense mutation-associated invasive breast cancer

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β

Identification of immune-related lncRNAs in peripheral blood of sepsis by transcriptome sequencing and analysis core lncRNA PRKCQ-AS1 roles in prognosis and progression of sepsis

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