Schizophrenia-associated rs4702 G allele-specific downregulation of FURIN expression by miR-338-3p reduces BDNF production

Hou, Yu; Liang, Wenquan; Zhang, Jian; Li, Qiyang; Ou, Haiyan; Wang, Zhongju; Li, Shufen; Huang, Xingbing; Zhao, Cunyou

doi:10.1016/j.schres.2018.02.040

Cited by 40 publications

(31 citation statements)

References 21 publications

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“…CASC2c could influence macrophage polarization, but miR-338-3p could not. miR338-3p can target many proteins such as MMP2, MMP9 ( 70 ), BDNF ( 71 ), Sphk2 ( 72 ), and IRS2 ( 73 ). BDNF enriched in glioma environment stimulated the production of IL-15 in CD11b + macrophages cells and altered macrophage plasticity ( 74 ).…”

Section: Discussionmentioning

confidence: 99%

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

Zhang

Feng

et al. 2018

Front. Immunol.

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Tumor-associated macrophages (TAMs) constitute a major component of inflammatory cells in the glioblastoma multiforme (GBM) tumor microenvironment. TAMs have been implicated in GBM angiogenesis, invasion, local tumor recurrence, and immunosuppression. Coagulation factor X (FX) is a vitamin K-dependent plasma protein that plays a role in the regulation of blood coagulation. In this study, we first found that FX was highly expressed and positively correlated with TAM density in human GBM. FX exhibited a potent chemotactic capacity to recruit macrophages and promoted macrophages toward M2 subtype polarization, accelerating GBM growth. FX bound to extracellular signal-related kinase (ERK)1/2 and inhibited p-ERK1/2 in GBM cells. FX was secreted in the tumor microenvironment and increased the phosphorylation and activation of ERK1/2 and AKT in macrophages, which may have been responsible for the M2 subtype macrophage polarization. Moreover, although the lncRNA CASC2c has been verified to function as a miR-101 competing endogenous RNA (ceRNA) to promote miR-101 target genes in GBM cells, we first confirmed that CASC2c did not function as a miR-338-3p ceRNA to promote FX expression, and that FX was a target gene of miR-338-3p. CASC2c interacted with and reciprocally repressed miR-338-3p. Both CASC2c and miR-388-3p bound to FX and commonly inhibited its expression and secretion. CASC2c repressed M2 subtype macrophage polarization. Taken together, our findings revealed a novel mechanism highlighting CASC2c and FX as potential therapeutic targets to improve GBM patients by altering the GBM microenvironment.

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Section: Discussionmentioning

confidence: 99%

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

Zhang

Feng

et al. 2018

Front. Immunol.

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“…Seventeen genes showed posterior probability of colocalization using coloc 7 (PP(H 4 )) >0.7 (Table 3), with 3 showing PP(H 4 ) > 0.95 (FURIN, ZNF823, RP11-677M14.2). FURIN, having previously identified as a candidate through colocalization 24 has recently been shown to reduce brain-derived neurotrophic factor (BDNF) maturation and secretion when inhibited by miR-338-3p 41 . ZNF823 has been identified in previous colocalization analyses 42,43 .…”

Section: Resultsmentioning

confidence: 99%

Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions

Sieberts

Perumal

Carrasquillo

et al. 2019

Preprint

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words maximum)The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes), and provide the results as a community resource. We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. In addition, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a common resource for use across the community in research programs. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia SKS, SM, MP, PLDJ, NET, LMM, the AMP-AD Consortium, and the CMC Consortium contributed to the design and generation of the study data.

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“…Together with the data shown here, this suggests that CD147 protein may enhance viral entry by means other than directly binding to or modifying SARS-CoV-2, that it may require a secondary cofactor, and/or that CD147 has cell-type-specific functions in vivo. The impact of FURIN expression was not unexpected (Coutard et al, 2020;Wrapp et al, 2020); however, because rs4702 lies in the binding site for microRNA-338 (Hou et al, 2018), this is a contextdependent eQTL, and so dependent upon cell-type-specific and donor-dependent expression of miR-338 (Schrode et al, 2019). Overall, it remains possible that our in vitro findings will not predict clinical response because of the influence of other genetic and/or environmental factors.…”

Section: Discussionmentioning

confidence: 83%

Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

Dobrindt

Hoagland

Seah

et al. 2020

Preprint

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The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying co-morbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants also impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population at large, and located in the 3’UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in SARS-CoV-2. Ongoing genetic studies will help to better identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs that might treat disease.

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Schizophrenia-associated rs4702 G allele-specific downregulation of FURIN expression by miR-338-3p reduces BDNF production

Cited by 40 publications

References 21 publications

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

Coagulation Factor X Regulated by CASC2c Recruited Macrophages and Induced M2 Polarization in Glioblastoma Multiforme

Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions

Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

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