RNA-seq in imprinted vs naive Omicron-positive volunteers
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PROVIDER: PRJEB74628 | ENA |
REPOSITORIES: ENA
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Project description:Naive pluripotent epiblast cells of the preimplantation murine embryo and their in vitro counterpart, embryonic stem (ES) cells, have the capacity to give rise to all cells of the adult. Such developmental plasticity is associated with global genome hypomethylation. It is unclear whether genome methylation is dynamically regulated only via differential expression of DNA methyltransferases (DNMTs) and Ten-eleven Translocation (TET) enzymes, which oxidase methylated DNA. Here we show that LIF/Stat3 signalling induces genomic hypomethylation via metabolic reconfiguration. In Stat3-/- ES cells we observed decreased alpha-ketoglutarate (ɑKG) production from reductive Glutamine metabolism, leading to decreased TET activity, increased Dnmt3a/b expression and to a global increase in DNA methylation. Notably, genome methylation is dynamically controlled by simply modulating αKG availability, mitochondrial activity or Stat3 activation in mitochondria, indicating effective crosstalk between metabolism and the epigenome. Stat3-/- ES cells also show increased methylation at Imprinting Control Regions accompanied with differential expression of >50% of imprinted genes. Single-cell transcriptome analysis of Stat3-/- embryos confirmed dysregulated expression of Dnmt3a/b, Tet2, and imprinted genes in vivo. Our results reveal that the LIF/Stat3 signal bridges the metabolic and epigenetic profiles of naive pluripotent cells, ultimately controlling genome methylation and imprinted gene expression. Several imprinted genes regulate cell proliferation and are often misregulated in tumors. Moreover, a wide range of cancers display Stat3-overactivation, raising the possibility that the molecular module we described here is exploited under pathological conditions.
2020-11-26 | PXD020385 | Pride
Project description:Metabolic control of imprinted gene expression in naive pluripotent cells
| PRJNA555434 | ENA
Project description:In this experiment we generated Affymetrix gene expression data for T Follicular Helper (TFH) cells from tonsils of healthy volunteers (4 biological replicates) and naive CD4-positive helper T cells (2 biological replicates). TFH cells provide a model relevant to SLE as TFH operate upstream of the activation of pathogenic autoantibody-producing B cells during the disease. This experiment accompanies promoter capture-C and ATAC-seq experiments on the same cell types.
2019-04-01 | E-MTAB-6637 | biostudies-arrayexpress
Project description:Naive pluripotent epiblast cells of the preimplantation embryo and their in vitro counterpart, naive murine embryonic stem (ES) cells , are characterised by global DNA hypomethylation. This is caused by elevated expression of TETs oxidases and by downregulation of DNA methyltransferases (DNMTs). However, the signal orchestrating such dynamic changes in vitro and in vivo are only partially understood. Here we report that Stat3 induces genomic hypomethylation via metabolic reconfiguration. In Stat3 -/- ES cells we observed reduced alpha-ketoglutarate (ɑKG) production from reductive glutaminolysis. This is accompanied by reduced levels of Tet2 and its product, hydroxy-methyl-cytosine, together with increased Dnmt3a/b expression and methyl-cytosine levels. Notably, genome methylation can be dynamically controlled by simply modulating αKG availability, mitochondrial activity or Stat3 activation. Stat3-/- ES cells show also general increased methylation at Imprinting Control Regions accompanied with differential expression of >60% of imprinted genes. Several of them, including Lin28a, Ndn and Peg10, are normally upregulated during differentiation, and displayed anticipated and enhanced expression in Stat3-/- cells, indicating faster differentiation kinetics. Single-cell transcriptome analysis of Stat3-/- embryos confirmed dysregulated expression of Dnmt3a/b, Tet2, imprinted genes and anticipated expression of differentiation markers. Our results reveal that Stat3 bridges the metabolic and epigenetic profiles of naive pluripotent cells and may be relevant under Stat3-dependent pathological conditions.
2020-11-30 | GSE134450 | GEO
Project description:Genome Wide Association Studies (GWAS) have been successful in yielding >60 loci for Systemic Lupus Erythematosus (SLE). However, it is known that GWAS just reports genomic signals and not necessarily the precise localization of culprit genes, with eQTL efforts only able to infer causality to a minority of such loci. Thus, we sought to carry out physical and direct ‘variant to gene mapping’ by integrating results from high-throughput chromatin conformation capture and ATAC-seq assays. This experiment refers to the ATAC-seq part of our work. To determine informative proxy SNPs for each of the SLE GWAS sentinel loci, we generated ATAC-seq open chromatin maps for primary human T Follicular Helper (TFH) cells from tonsils of healthy volunteers (3 biological replicates), a model relevant to SLE as TFH operate upstream of the activation of pathogenic autoantibody-producing B cells during the disease. We also generated open chromatin maps for naive CD4-positive helper T cells (3 biological replicates).
2020-05-12 | E-MTAB-6617 | biostudies-arrayexpress
Project description:The Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in November 2021 in South Africa, has initiated the 5th wave of global pandemics. Here, we systemically examined immunological and metabolic characteristics of Omicron variants infection. We found Omicron resisted to neutralizing antibody targeting receptor binding domain (RBD) of wild-type SARS-CoV-2. Omicron could not be neutralized by sera of Corona Virus Disease 2019 (COVID-19) convalescent individuals who were infected with the Delta variant. Through mass spectrometry on MHC-bound peptidomes, we found that the spike protein of the Omicron variants could generate additional CD8+ T cell epitopes, compared with Delta. These epitopes could induce robust CD8+ T cell responses. Moreover, we found booster vaccination increased the cross-memory CD8+ T cell responses against Omicron. Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted memory T cell responses. Consistently, a higher fraction of memory CD8+ T cells were found in Omicron stimulated peripheral blood mononuclear cells (PBMCs). In addition, CD147 was also a receptor for the Omicron variants, and CD147 antibody inhibited infection of Omicron. CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia. Taken together, our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.
2023-03-11 | PXD037955 | Pride
Project description:Antibody response following Omicron infection is reported to be less robust than that to other variants. Here we investigated how prior vaccination and/or prior infection modulates that response. Disease severity, antibody responses and immune transcriptomes were characterized in four groups of Omicron-infected outpatients (n=83): unvaccinated/no prior infection, vaccinated/no prior infection, unvaccinated/prior infection and vaccinated/prior infection. The percentage of patients with asymptomatic or mild disease was highest in the vaccinated/no prior infection group (87%) and lowest in the unvaccinated/no prior infection group (47%). Significant anti-Omicron spike antibody levels and neutralizing activity were detected in the vaccinated group immediately after infection but were not present in the unvaccinated/no prior infection group. Within two weeks, antibody levels against Omicron, increased. Omicron neutralizing activity in the vaccinated group exceeded that of the prior infection group. No increase in neutralizing activity in the unvaccinated/no prior infection group was seen. The unvaccinated/prior infection group showed an intermediate response. We then investigated the early transcriptomic response following Omicron infection in these outpatient populations and compared it to that found in unvaccinated hospitalized patients with Alpha infection. Omicron infected patients showed a gradient of transcriptional response dependent upon whether or not they were previously vaccinated or infected. Vaccinated patients showed a significantly blunted interferon response as compared to both unvaccinated Omicron infected outpatients and unvaccinated Alpha infected hospitalized patients typified by the response of specific gene classes such as OAS and IFIT that control anti-viral responses and IFI27, a predictor of disease outcome.
2022-06-11 | GSE201530 | GEO
Project description:SARS-CoV-2 Omicron infection results in a milder clinical feature compared to the Delta strain. The development of Omicron specific vaccine has also been hampered due to the low immunogenicity. By reverse-mutating the amino acids in the Omicron receptor binding domain (RBD), we identified that the mutation from Phenylalanine 375 (F375) in the Omicron spike to Serine 375 (S375) in Delta and other early strains significantly enhances the immune response in the manner of vaccines. Interestingly, the new evolution of the 371FAPF375FAF sequence in Omicron exhibited a potent inhibitory effect on macrophage uptake of the RBD nanoparticle or spike-pseudovirus particles. Omicron RBD enhances binding to Siglec-9 on macrophages to reduce the immunogenicity and increase the immune evasion, which could be abrogated by Serine 375 mutation. Based upon these observations, we further developed a bivalent Omicron RBD with S375 mutation and Delta RBD nanoparticle vaccine, which elicited potent and broad neutralizing antibodies in mice, rabbits, and rhesus macaques. Our research suggests that manipulating the Siglec-9 pathway could be a promising approach to enhancing vaccine response. Importantly, our findings suggest that Omicron subvariants have developed a new strategy to evade immune surveillance by impairing the phagocytosis and antigen presentation processes of macrophages.
2023-12-28 | GSE251973 | GEO
Project description:naive T vs conA treated sample
| PRJNA950948 | ENA
Project description:Genome Wide Association Studies (GWAS) have been successful in yielding >60 loci for Systemic Lupus Erythematosus (SLE). However, it is known that GWAS just reports genomic signals and not necessarily the precise localization of culprit genes, with eQTL efforts only able to infer causality to a minority of such loci. Thus, we sought to carry out physical and direct ‘variant to gene mapping’ by integrating results from high-throughput chromatin conformation capture and ATAC-seq assays. This experiment refers to the chromatin conformation capture part of our work. Detecting contacts between distant regions of the genome offers a powerful opportunity to understand GWAS signals that principally reside in non-coding regions, and thus likely act as regulatory elements for neighboring genes. To move beyond analyzing one locus at a time and to improve on the low resolution of available Hi-C data, we employed a massively parallel, high resolution Capture-C based method to simultaneously characterize the genome-wide interactions of all human promoters in any cell type. We applied this approach to study the promoter ‘interactome’ of primary human T Follicular Helper (TFH) cells from tonsils of healthy volunteers (3 biological replicates), a model relevant to SLE as TFH operate upstream of the activation of pathogenic autoantibody-producing B cells during the disease. We also analyzed the promoter interactome of naive CD4-positive helper T cells (3 biological replicates). We designed a custom Agilent SureSelect library targeting both ends of DpnII restriction fragments that overlap promoters of protein-coding, noncoding, antisense, snRNA, miRNA, snoRNA and lincRNA transcripts. Each library was sequenced on 8 lanes of an Illumina HiSeq 4000.
2020-05-12 | E-MTAB-6621 | biostudies-arrayexpress