Severe type 1 interferonopathy due to germline STAT2 gain-of-function
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ABSTRACT:
PROVIDER: PRJEB29090 | ENA |
REPOSITORIES: ENA
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Project description:The transcription factor STAT2 is essential for transcriptional activation downstream of the receptors for the innate IFNs -α/β (IFNAR) and -gamma (IFNLR). STAT2 is activated by tyrosine phosphorylation, associating with STAT1 and IRF9 to form the Interferon-Stimulated Gene Factor 3 (ISGF3) to effect gene transcription. Loss-of-function variants in STAT2 increase susceptibility to viral disease. Here a transcriptome study is reported on an individual with severe early-onset neuroinflammatory disease and an elevated IFN signature. The individual had a homozygous missense variant in STAT2 and symptoms consistent with a gain-of-function effect.
2019-11-06 | E-MTAB-7275 | biostudies-arrayexpress
Project description:RNA-seq of human donors with severe type 1 interferonopathy due to germline STAT2 gain-of-function
| PRJEB41073 | ENA
Project description:Patients with type 1 interferonopathies due to mutations in one of 10 genes were recruited over the course of 4 years. All patients had raised levels of interferon stimulated genes as determined by qPCR. A transcriptome analysis was carried out to compare levels of interferon stimulated genes in the patient with a mutation in STAT2, compared to patients with mutations in other interferonopathy genes.
2020-11-03 | E-MTAB-9722 | biostudies-arrayexpress
Project description:Excessive type I interferon (IFN?/?) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFN?/?, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN?/? signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN?/? signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN?/? activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
| S-EPMC7115903 | biostudies-literature
Project description:Germline hypomorphic CARD11 mutations in severe atopic disease
| PRJNA386065 | ENA
Project description:Influenza is the common respiratory problem that infects between 5-20% of the US population and results in 30,000 deaths annually. A primary cause of the influenza-associated death is due to secondary bacterial pneumonia. In this study, we investigated the role of STAT2 signaling during influenza and influenza-bacterial super-infection in mice. Herein, we demonstrate that STAT2 signaling is required for viral control, regulation of inflammation, and limiting mortality during influenza single infection. Surprisingly, despite this deficiency in anti-viral immunity, we found increased bacterial control and survival in STAT2 deficient mice during influenza-MRSA super-infection compared to controls. This protection in the absence of STAT2 was associated with accumulation of dual phenotype M1/M2 macrophages, which were required for control of bacterial infection. Together, these results suggest that the STAT2 signaling is involved in suppressing macrophage activation and bacterial control during influenza-bacterial super-infection.
2018-12-26 | GSE119029 | GEO
Project description:STAT2 is an essential transcription factor in type I interferon (IFN) signaling. STAT2 is activated following exposure to IFN stimulation by phosphorylation at tyrosine-690. This post-translational modification permits the assembly and nuclear retention of the ISGF3 complex (consisting of STAT1/STAT2/IRF9) to drive gene transcription. We recently identified STAT2 to be serine phosphorylated in an IFN-dependent manner. The biological significance of these novel phosphorylation events in STAT2 remain to be elucidated. Thus far our data show that serine phosphorylation of STAT2 negatively regulates the biological effects of IFN. In an effort to understand the scope of STAT2 serine phosphorylation in IFN signaling, we conducted comparative microarray analysis to identify a collection of genes that are regulated by phosphorylated Ser734-STAT2 vs. unphosphorylated S734-STAT2 after IFN treatment.
2015-10-01 | GSE57017 | GEO
Project description:In C. elegans, the H3K4me2 demethylase, SPR-5, and the H3K9 methyltransferase, MET-2, are maternally deposited into the oocyte where they reprogram histone methylation to prevent somatic expression of germline genes. Here, we show that the progeny of spr-5; met-2 mutants display a severe developmental delay that is associated with the ectopic expression of germline genes targeted by the H3K36me2/3 methyltransferase, MES-4. Maternally deposited MES-4 maintains H3K36me2/3 at a subset of germline genes (hereafter referred to as MES-4 germline genes) in a transcription-independent manner, and this is required for germline proliferation in the subsequent generation. By performing ChIP-seq on L1 progeny from spr-5; met-2 mutants, we find that MES-4 germline genes ectopically accumulate H3K36me3 in somatic tissues. Additionally, knocking down MES-4 suppresses the ectopic expression of MES-4 germline genes and rescues the developmental delay. These data suggest a model where SPR-5, MET-2 and MES-4 carefully balance the inheritance of histone methylation from the parental germline to ensure the proper specification of germline versus soma in the progeny. Without SPR-5; MET-2 maternal reprogramming, somatic cells struggle to specify their proper cell fate amongst the background noise of inappropriate germline gene transcription, leading to a severe developmental delay.
2020-05-29 | GSE151340 | GEO
Project description:We descrie a cohort of 10 families, with 16 patients, that presented with severe early onset allergic disease since birth. Disease inhertance was in an autosomal dominant manner and heterozygous variants in STAT6 were identified in all patients. Whole blood bulk RNAsequencing was done on patient 6 to understand treatment specific transcriptomic changes in this patient.
2023-02-20 | GSE222646 | GEO
Project description:Our previous study revealed that the transcription factor STAT2 promoted the growth of colorectal tumors, but the molecular mechanisms by which STAT2 contributes to tumor promotion are still unknown. Given that alterations in the tumor suppressor p53 gene are very common in colorectal cancer and critical in adenoma-carcinoma transition, we investigated whether STAT2 may also be implicated in disease progression when normal p53 function is disabled. We found Stat2 silencing in colon cancer cells deficient in p53 reduced the capacity of tumor cells to migrate and invade in vitro. We also determined that Stat2 silencing impaired tumor cells to metastasize to the liver. To begin to understand how STAT2 contributes to disease progression, we performed RNA-Seq analysis on colon tumor xenografts with the purpose to identify a STAT2 transcriptome. From this study, we identified a subset of STAT2 regulated genes that in future studies will confirm their role in colon carcinogenesis.
2020-11-17 | GSE137155 | GEO