Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined
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ABSTRACT:
PROVIDER: PRJNA493634 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7938630.fastq.gz | Fastqsanger.gz | |||
| SRR7938631.fastq.gz | Fastqsanger.gz | |||
| SRR7938632.fastq.gz | Fastqsanger.gz | |||
| SRR7938633.fastq.gz | Fastqsanger.gz | |||
| SRR7938634.fastq.gz | Fastqsanger.gz |
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Project description:STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. STAT1 GOF mutations result in hyperphosphorylation and delayed dephosphorylation of STAT1. However, how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α in STAT1 GOF patients were not persistently elevated. Nevertheless, the interferon signature was evident even in the patient with low or undetectable IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments showed that the active chromatin mark H3K4me3, was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to normal cells. This suggests that GOF STAT1, while binding to chromatin, promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and interferon-related autoimmunity. We suggest that epigenetic rewiring may be responsible for treatment failure of JAK1/2 inhibitors in certain patients. We also found that after IL-21 stimulation the balance of p-STAT3/p-STAT1 was significantly impaired in patients, which could potentially be applied as a diagnostic test for STAT1 GOF.
2019-05-31 | GSE120580 | GEO
Project description:To investigate the effect of STAT1 gain of function on gene expression in CD4+ T cells, we sorted TCRβ+CD4+ CD44+ T cells from the spleens of STAT1 gain of function (STAT1 GOF/CMV Cre) and wild type C57BL/6J control mice of the same sexe by cell sorting.
2023-11-22 | GSE218608 | GEO
Project description:Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease, and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (IFN) stimulation, is seen consistently in all patients and may not fully account for the broad phenotypic spectrum associated with this disorder. While over 100 mutations have been implicated in STAT1 GOF, genotype-phenotype correlation remains limited, and current overexpression models may be of limited use in gene expression studies. We generated heterozygous mutants in diploid HAP1 cells using CRISPR/Cas9 base-editing, targeting the endogenous STAT1 gene. Our models recapitulated the molecular phenotype of elevated pSTAT1, and were used to characterize the expression of five IFN-stimulated genes under a number of conditions. At baseline, transcriptional polarization was evident among mutants compared with wild type, and this was maintained following prolonged serum starvation. This suggests a possible role for unphosphorylated STAT1 in the pathogenesis of STAT1 GOF. Following stimulation with IFNα or IFNγ, differential patterns of gene expression emerged among mutants, including both gain and loss of transcriptional function. This work highlights the importance of modeling heterozygous conditions, and in particular transcription factor-related disorders, in a manner which accurately reflects patient genotype and molecular signature. Furthermore, we propose a complex and multifactorial transcriptional profile associated with various STAT1 mutations, adding to global efforts in establishing STAT1 GOF genotype-phenotype correlation and enhancing our understanding of disease pathogenesis.
| S-EPMC8121859 | biostudies-literature
Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape. mRNAs from cells expressing the siRNA siRNA duplexes targeting hCAF1, corresponding to the coding region 941-961 (kd) (hCAF1 NCBI Reference Sequence: NM_013354.5) and one non-targeting control siRNA (mock).
2013-12-31 | E-GEOD-43334 | biostudies-arrayexpress
Project description:STAT1 gain-of-function (GOF) is a primary immunodeficiency typically characterized by chronic mucocutaneous candidiasis (CMC), recurrent respiratory infections and autoimmunity. Less commonly, also immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX)-like syndromes with CMC, and combined immunodeficiency without CMC have been described. Recently, our group and others have shown that different mutation-specific mechanisms underlie STAT1 GOF in vitro, including faster nuclear accumulation (R274W), and reduced mobility (R321, N574I) to near immobility in the nucleus (T419R) upon IFNγ stimulation. In this work, we evaluated the transcriptomic fingerprint of the aforementioned STAT1 GOF mutants (R274W, R321S, T419R, and N574I) relative to STAT1 wild-type upon IFNγ stimulation in an otherwise isogenic cell model. The majority of genes up-regulated in wild-type STAT1 cells were significantly more up-regulated in cells expressing GOF mutants, except for T419R. In addition to the common interferon regulated genes (IRG), STAT1 GOF mutants up-regulated an additional set of genes, that were in part shared with other GOF mutants or mutation-specific. Overall, R274W and R321S transcriptomes clustered with STAT1 WT, while T419R and N574I had a more distinct fingerprint. We observed reduced frequency of canonical GAS sequences in promoters of genes up-regulated by all the STAT1 GOF mutants, suggesting loss of DNA binding specificity for the canonical GAS consensus. Interestingly, the T419R mutation, expected to directly increase the affinity for DNA, showed the most pronounced effects on the transcriptome. T419R STAT1 dysregulated more non-IRG than the other GOF mutants and fewer GAS or degenerate GAS promotor sequences could be found in the promoter regions of these genes. In conclusion: our work confirms hyperactivation of common sets of IFNγ-induced genes in STAT1 GOF with additional dysregulation of mutation-specific genes, in line with the earlier observed mutation-specific mechanisms. Binding to more degenerate GAS sequences is proposed as a mechanism towards transcriptional dysregulation in R274W, R321S, and N574I. For T419R, an increased interaction with the DNA is suggested to result in a broader and less GAS-specific response. Our work indicates that multiple routes leading to STAT1 GOF are associated with common and private transcriptomic fingerprints, which may contribute to the phenotypic variation observed in vivo.
2021-02-09 | GSE166392 | GEO
Project description:STAT1 plays a cental role in the induction of interferon-stimulated genes, but interferon alpha can activate a STAT1-independent pathway that leads to gene expression. We performed microarray analysis to examine whether like interferon alpha, interferon lambda, a newly discovered interferon, can induce the expression of interferon-stimulated genes in the absence of STAT1. Control and STAT1 knockout Huh-7.5 hepatoma cells were left untreated or treated with 1000 U/ml of human interferon alpha 2a or interferon lambda 1 (PBL) for 24 h, and total RNA was extracted. Sense-strand DNA was generated from 200 ng of total RNA, fragmented, and labeled using a GeneChip WT Plus Reagent Kit (Affymetrix). Six samples were obtained and each sample was anlyzed using one GeneChip.
2016-07-22 | E-GEOD-84693 | biostudies-arrayexpress
Project description:Interferonopathies drive autoimmunity but can also impair host responses to pathogens including viral infection. To better understand viral susceptibility of patients with STAT1 gain-of-function (GOF) mutations, we generated conditional-knockin mouse models to elucidate disease mechanisms and relevance of different immune subsets. Virally infected Stat1-GOF mice exhibited impaired early IFN-γ production from innate lymphocytes, and lethality due to excess prolonged multi-cytokine production. The presence of the Stat1-GOF allele resulted in premature usage of interferon-stimulated gene factor 3 (ISGF3) over the normal Stat4/AP-1 dependent transcriptomic program in activated innate lymphocytes. Administration of anti-IFN-γantibodies in wild-type (WT) mice after infection phenocopied Stat1-GOF mice presenting exaggerated inflammation despite viral control. Conversely, early administration of exogenous IFN-γ to infected Stat1-GOF mice prevented lethality and exaggerated cytokine response.Although Stat1-GOF mutations facilitate IFN-γ-mediated autoimmunity, early IFN-γ response to viral infection via a normal Stat4 program was impaired, leading to overcompensated inflammatory responses in Stat1-GOF mice.
2025-06-13 | GSE284322 | GEO
Project description:Interferonopathies drive autoimmunity but can also impair host responses to pathogens including viral infection. To better understand viral susceptibility of patients with STAT1 gain-of-function (GOF) mutations, we generated conditional-knockin mouse models to elucidate disease mechanisms and relevance of different immune subsets. Virally infected Stat1-GOF mice exhibited impaired early IFN-γ production from innate lymphocytes, and lethality due to excess prolonged multi-cytokine production. The presence of the Stat1-GOF allele resulted in premature usage of interferon-stimulated gene factor 3 (ISGF3) over the normal Stat4/AP-1 dependent transcriptomic program in activated innate lymphocytes. Administration of anti-IFN-γantibodies in wild-type (WT) mice after infection phenocopied Stat1-GOF mice presenting exaggerated inflammation despite viral control. Conversely, early administration of exogenous IFN-γ to infected Stat1-GOF mice prevented lethality and exaggerated cytokine response.Although Stat1-GOF mutations facilitate IFN-γ-mediated autoimmunity, early IFN-γ response to viral infection via a normal Stat4 program was impaired, leading to overcompensated inflammatory responses in Stat1-GOF mice.
2025-06-13 | GSE284176 | GEO
Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape.
2013-12-31 | GSE43334 | GEO
Project description:Interferonopathies drive autoimmunity but can also impair host responses to pathogens including viral infection. To better understand viral susceptibility of patients with STAT1 gain-of-function (GOF) mutations, we generated conditional-knockin mouse models to elucidate disease mechanisms and relevance of different immune subsets. Virally infected Stat1-GOF mice exhibited impaired early IFN-γ production from innate lymphocytes, and lethality due to excess prolonged multi-cytokine production. The presence of the Stat1-GOF allele resulted in premature usage of interferon-stimulated gene factor 3 (ISGF3) over the normal Stat4/AP-1 dependent transcriptomic program in activated innate lymphocytes. Administration of anti-IFN-γantibodies in wild-type (WT) mice after infection phenocopied Stat1-GOF mice presenting exaggerated inflammation despite viral control. Conversely, early administration of exogenous IFN-γ to infected Stat1-GOF mice prevented lethality and exaggerated cytokine response.Although Stat1-GOF mutations facilitate IFN-γ-mediated autoimmunity, early IFN-γ response to viral infection via a normal Stat4 program was impaired, leading to overcompensated inflammatory responses in Stat1-GOF mice.
2025-06-13 | GSE284323 | GEO