Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA385770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5515150.fastq.gz | Fastqsanger.gz | |||
| SRR5515160.fastq.gz | Fastqsanger.gz | |||
| SRR5515151.fastq.gz | Fastqsanger.gz | |||
| SRR5515161.fastq.gz | Fastqsanger.gz | |||
| SRR5515152.fastq.gz | Fastqsanger.gz |
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Project description:The treatment of chronic mucocutaneous ulceration is challenging and only some patients respond selectively to inhibitors of tumor necrosis factor-alpha (TNF-a). TNF-a activates opposing pathways leading to caspase-8-mediated apoptosis as well as NF-kB-dependent cell survival. We investigated the etiology of autosomal dominant mucocutaneous ulceration in a family whose proband was dependent on anti-TNF-a therapy for sustained remission. A heterozygous mutation in RELA (NM_021975: c.559+1G>A), encoding the NF-kB subunit RelA (p65), segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients’ fibroblasts exhibited increased apoptosis in response to TNF-a, impaired NF-kB activation, and defective expression of NF-B-dependent anti-apoptotic genes. We show that Rela+/- mice have similarly impaired NF-kB activation, develop cutaneous ulceration from TNF-a exposure, and exhibit severe dextran sodium sulfate-induced colitis ameliorated by TNF-a inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-a-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF-a inhibition in this disease.
2017-05-09 | GSE98624 | GEO
Project description:Rationale- NAA15 is a component of the N-terminal (Nt) acetyltransferase complex, NatA. The mechanism by which NAA15 haploinsufficiency causes congenital heart disease (CHD) remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective- We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity, and identifying proteins dependent upon a full amount of NAA15.Methods and Results - We introduced heterozygous LoF, compound heterozygous and missense residues (R276W) in iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to altered composition of NatA. Mass spectrometry (MS) analyses reveal ~80% of identified iPS cell NatA targeted proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells Nt-acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W iPSCs. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; eighteen were ribosomal-associated proteins. At least four proteins were encoded by genes known to cause autosomal dominant CHD. Conclusions - These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and Nt-acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated CHD. Additionally, genetically engineered iPS cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.
2020-11-05 | GSE160809 | GEO
Project description:Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTD) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a novel CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients’ fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients’ TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients’ CMC. Consistently, the patients’ fibroblasts displayed impaired JNK1- and c-Jun/ATF2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome and mutations of TGFBR2 or SMAD3, further accounting for the patients’ complex and unusual CTD phenotype. This experiment of Nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida, and for the TGF-β-dependent homeostasis of connective tissues.
2019-11-29 | GSE137108 | GEO
Project description:Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTD) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a novel CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients’ fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients’ TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients’ CMC. Consistently, the patients’ fibroblasts displayed impaired JNK1- and c-Jun/ATF2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome and mutations of TGFBR2 or SMAD3, further accounting for the patients’ complex and unusual CTD phenotype. This experiment of Nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida, and for the TGF-β-dependent homeostasis of connective tissues.
2019-11-29 | GSE137107 | GEO
Project description:USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of >200 T-ALL transcriptomes linked USP7 haploinsufficiency with decreased activities of E-proteins. E-proteins are also negatively regulated by TAL1, leading to concerted down-regulation of E-protein target genes involved in T-cell development. In T-ALL cell lines, we show the physical interaction of USP7 with E-proteins and TAL1 by mass spectrometry and ChIP-seq. Haploinsufficient but not complete CRISPR knock-out of USP7 shown accelerated cell growth and validated transcriptional down-regulation of E-protein targets. Our study unveiled the synergistic effect of USP7 haploinsufficiency with aberrant TAL1 activation on T-ALL, implicating USP7 as a haploinsufficient tumor suppressor in T-ALL.
2021-03-16 | PXD023377 | Pride
Project description:Mutations in CHCHD10, coding for a mitochondrial intermembrane space protein, are a rare cause of autosomal dominant amyotrophic lateral sclerosis (ALS). Mutation-specific toxic gain of function or haploinsuffuciency models have been proposed to explain pathogenicity. To decipher the metabolic dysfunction associated with the haploinsufficient p.R15L variant we conducted a TMT labelling experiment. Fibroblasts with the CHCHD10 p.R15L variant (hereafter referred to as ‘patient’), were compared to the same cells expressing wild-type CHCHD10 cDNA (hereafter called ‘rescue’) under nutrient stress, in which galactose was substituted for glucose.
2022-04-04 | PXD018806 | Pride
Project description:Using CRISPR/Cas9 to generate an hiPSC line with SETD1A haploinsufficiency and differentiating it into glutamatergic and GABAergic neurons, we found that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was predominantly defined by increased network burst frequency, whereas unchanged global firing activity. In individual neurons, this network phenotype was reflected functionally by increased synchronized synaptic inputs and structurally by increased somatodendritic complexity in both glutamatergic and GABAergic neurons. The transcriptome profile in SETD1A haploinsufficient neurons demonstrated perturbations in gene sets associated with schizophrenia, synaptic transmission, and glutamatergic synaptic function. In addition, transcriptomic data suggested cAMP/PKA pathway might be disturbed in SETD1A haploinsufficient networks, which was further verified by pharmacological experiments.
2021-07-23 | GSE180648 | GEO
Project description:Human JNK1 haploinsufficiency: a novel genetic etiology of chronic mucocutaneous candidiasis and connective tissue disorder
| PRJNA564560 | ENA