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Single-cell multi-omics sequencing reveals the functional regulatory landscape of STAT3-V637M Hyper-IgE syndrome

ABSTRACT: Single-cell multi-omics sequencing reveals the functional regulatory landscape of STAT3-V637M Hyper-IgE syndrome

PROVIDER: PRJNA875484 | ENA |

REPOSITORIES: ENA

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Single-cell multi-omics sequencing reveals the functional regulatory landscape of STAT3-V637M Hyper-IgE syndrome

Project description:Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by, among others, the excessive production of IgE and repetitive bacterial/fungal infections. Although STAT3 is a known causative factor of HIES, the biological consequences of STAT3 mutation are not completely understood, especially at the epigenetic level. Here, we used multi-omic approaches to decipher the multidimensional immune disturbance in a male HIES patient harboring STAT3-V637M. In his peripheral blood mononuclear cell (PBMC) we found significant clonal expansion of CD8 T cells (whose expression of CD8 subunits was increased, resulting in enhanced responsiveness to MHC I molecules), but not CD4 T cells and B cells in his. The lack of T cells-B cells interaction could be responsible for the limited number of his B cells, although they exhibited a higher potential in producing immunoglobulin, elevated SPIC binding might bias this process toward IgE isotype production. Immune checkpoint inhibitors, including CTLA4, LAG3, were overexpressed in his PBMC-CD4 T cells, accompanied by reduced CD28 and IL6ST (gp130) expression. For his CD4 T cells, integrative analyses predicted upstream transcription factors (ETV6, KLF13, and RORA) for LAG3, IL6ST, and CD28, respectively. The down-regulated phagocytic, and nitric oxide synthetic genes in his PBMC-monocytes seem to be the culprit of his disseminated bacterial/fungal infection. In his bronchoalveolar lavage fluid (BALF), we identified two macrophages with anti-bacterial properties, which were characterized by CXCL8/S100A8/S100A9, or SOD2, respectively. Together, this study comprehensively described how the immune cell landscape was disturbed in STAT3-V637M HIES and provided a resource for further studies on STAT3 biology.

2023-09-07 | GSE212479 | GEO

Human ZNF341 deficiency underlies a recessive form of hyper IgE syndrome by disrupting STAT3 transcription-dependent STAT3 activity

Project description:Heterozygosity for human STAT3 dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-IgE syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including, most notably the STAT3 promoter. The patients’ cells have low basal levels of STAT3 mRNA and protein. The auto-induction of STAT3 production, activation, and function by STAT3-activating cytokines is particularly strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack Th17 cells, have an excess of Th2 cells, and low memory B cells, due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341-dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent auto-induction and sustained activity of STAT3.

2018-06-04 | GSE113945 | GEO

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

2018-05-30 | GSE113194 | GEO

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

Project description:Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

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A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Project description:A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

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Human ZNF341 deficiency underlies a recessive form of hyper IgE syndrome by disrupting STAT3 transcription-dependent STAT3 activity

Project description:Human ZNF341 deficiency underlies a recessive form of hyper IgE syndrome by disrupting STAT3 transcription-dependent STAT3 activity

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A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Project description:Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hy- per IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in re- cipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous pa- tients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when over- expressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phos- phorylation, DNA binding, and transcriptional activity. In immor- talized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding muta- tions, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequenc- ing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

2020-04-30 | GSE149602 | GEO

Gene expression analysis in endothelial cells derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

Project description:Autosomal-dominant hyper-IgE syndrome (AD-HIES, Job’s syndrome) is a primary immunodeficiency caused by loss of function mutations in signal transducer and activator of transcription 3 (STAT3), a critical regulator of diverse cellular processes. In addition to immunological deficits, patients experience severe non-immunological features including skeletal, connective tissue and vascular abnormalities, poor post-infection healing, and subsequent pulmonary failure. The underlying mechanisms of these STAT3-dependent non-immunological features are not understood, preventing the development of targeted treatments. In this study, global gene expression was analysed in the patients umbilical vein endothelial cells in order to identify signaling pathway affected by the disease-causing STAT3 mutations with ultimate goal to better understand the disease mechanism and identify promising therapeutic targets.

2020-08-12 | GSE139188 | GEO

Analysis of gene expression in skin fibroblasts derived from patients with Autosomal-dominant hyper-IgE syndrome (AD-HIES)

Project description:Autosomal-dominant hyper-IgE syndrome (AD-HIES, Job’s syndrome) is a primary immunodeficiency caused by loss of function mutations in signal transducer and activator of transcription 3 (STAT3), a critical regulator of diverse cellular processes. In addition to immunological deficits, patients experience severe non-immunological features including skeletal, connective tissue and vascular abnormalities, poor post-infection healing, and subsequent pulmonary failure. The underlying mechanisms of these STAT3-dependent non-immunological features are not understood, preventing the development of targeted treatments. In this study, global gene expression was analysed in the patients skin fibroblasts in order to identify signaling pathway affected by the disease-causing STAT3 mutations with ultimate goal to better understand the disease mechanism and identify promising therapeutic targets.

2020-08-12 | GSE139202 | GEO

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

Project description:A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

| PRJNA450407 | ENA