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Proteomic Analysis of Eosinophilic Esophagitis: Identification and Involvement of the Minichromosome Maintenance Complex as a Driver of Esophageal Basal Zone Hyperplasia

ABSTRACT: To uncover molecular drivers of Eosinophilic Esophagitis (EoE), a global proteome screen of the esophageal biopsies from individuals with and without EoE was performed.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Eosinophilic Esophagitis

SUBMITTER: Aleksandra Nita-Lazar

LAB HEAD: Aleksandra Nita-Lazar

PROVIDER: PXD040030 | Pride | 2023-08-01

REPOSITORIES: Pride

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			Action	DRS
	01_EoE1.raw	Raw
	02_NL1.raw	Raw
	03_NL2.raw	Raw
	04_EoE2.raw	Raw
	05_NL3.raw	Raw

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Proteomic analysis of the esophageal epithelium reveals key features of eosinophilic esophagitis pathophysiology

Project description:Background: Eosinophilic esophagitis (EoE) is a chronic non-IgE-mediated allergic disease of the esophagus. An unbiased proteomics approach was performed to investigate pathophysiological changes in esophageal epithelium. Additionally, an RNAseq-based transcriptomic analysis in paired samples was also carried out. Methods: Total proteins were purified from esophageal endoscopic biopsies in a cohort of adult EoE patients (n = 25) and healthy esophagus controls (n = 10). Differentially accumulated (DA) proteins in EoE patients compared to control tissues were characterized to identify altered biological processes and signaling pathways. Results were also compared with a quantitative proteome dataset of the human esophageal mucosa. Next, results were contrasted with those obtained after RNAseq analysis in paired samples. Finally, we matched up protein expression with two EoE-specific mRNA panels (EDP and Eso-EoE panel). Results: A total of 1667 proteins were identified, of which 363 were DA in EoE. RNA sequencing in paired samples identified 1993 differentially expressed (DE) genes. Total RNA and protein levels positively correlated, especially in DE mRNA-proteins pairs. Pathway analysis of these proteins in EoE showed alterations in immune and inflammatory responses for the upregulated proteins, and in epithelial differentiation, cornification and keratinization in those downregulated. Interestingly, a set of DA proteins, including eosinophil-related and secreted proteins, were not detected at the mRNA level. Protein expression positively correlated with EDP and Eso-EoE, and corresponded with the most abundant proteins of the human esophageal proteome. Conclusions: We unraveled for the first time key proteomic features involved in EoE pathogenesis. An integrative analysis of transcriptomic and proteomic datasets provides a deeper insight than transcriptomic alone into understanding complex disease mechanisms.

2025-04-11 | PXD062507 | Pride

The minichromosome maintenance complex drives esophageal basal zone hyperplasia.

Project description:Eosinophilic esophagitis (EoE) is a chronic gastrointestinal disorder characterized by food antigen-driven eosinophilic inflammation and hyperproliferation of esophageal mucosa. By utilizing a large-scale, proteomic screen of esophageal biopsies, we aimed to uncover molecular drivers of the disease. Proteomic analysis by liquid chromatography-tandem mass spectrometry identified 402 differentially expressed proteins (DEPs) that correlated with the EoE transcriptome. Immune cell-related proteins were among the most highly upregulated DEPs in EoE compared with controls, whereas proteins linked to epithelial differentiation were primarily downregulated. Notably, in the inflamed esophageal tissue, all 6 subunits of the minichromosome maintenance (MCM) complex, a DNA helicase essential for genomic DNA replication, were significantly upregulated at the gene and protein levels. Furthermore, treating esophageal epithelial cells with a known inhibitor of the MCM complex (ciprofloxacin) blocked esophageal epithelial proliferation. In a murine model of EoE driven by overexpression of IL-13, ciprofloxacin treatment decreased basal zone thickness and reduced dilated intercellular spaces by blocking the transition of epithelial cells through the S-phase of the cell cycle. Collectively, a broad-spectrum proteomic screen has identified the involvement of the MCM complex in EoE and has highlighted MCM inhibitors as potential therapeutic agents for the disease.

| S-EPMC10544209 | biostudies-literature

Clariom S Microarray Expression Data from Human Eosinophilic Esophagitis and Control Esophageal Biopsies

Project description:This study sought to evaluate the diffferential gene expression of human Eosinophilic Esophagitis (EoE) patients compared to control patients. Abstract from associated publication: Eosinophilic Esophagitis (EoE) is a chronic allergic disease characterized by progressive inflammation of the esophageal mucosa. While the transcriptome of EoE has been reported, few studies have examined the genetics among both adult and pediatric EoE populations. Here, we use microarray analysis to interrogate gene expression using esophageal biopsies from EoE and Control subjects with a wide age distribution. Analysis of differential gene expression and prediction of impaired pathways was compared using conventional transcriptome analysis programs and an artificial intelligence-based ADVAITA program. Principal Components Analysis revealed samples cluster by disease status (EoE and Control) irrespective of clinical features like sex, age, and disease severity. Global transcriptomic analysis revealed differential expression of several genes previously reported in EoE (CCL26, CPA3, POSTN, CTSC, ANO1, CRISP3, SPINK7). In addition, we identified differential expression of several genes from the MUC and SPRR families, which has not been previously reported. Our findings suggest their involvement in impaired barrier integrity and loss of epidermal cell differentiation in EoE patients. These findings present two new gene families that are differentially expressed in EoE patients in both adult and pediatric populations, which presents an opportunity for a future therapeutic targets that would be useful in a large demographic of patients.

2023-08-10 | GSE228083 | GEO

Analysis and expansion of the eosinophilic esophagitis transcriptome by RNA sequencing

Project description:We utilized RNA sequencing to expand and better define the molecular entities involved in the transcriptional programming within the eosphagus in eosinophilic esophagitis (EoE) Examination of differentially expressed genes from RNA sequencing data performed on esophageal biopsy specimen from 6 healthy controls and 10 patients with active EoE

2014-06-27 | E-GEOD-58640 | biostudies-arrayexpress

The EoE esophageal epithelial transcriptomic landscape

Project description:We report alterations in the esophageal transcriptome of adult eosinophilic esophagitis (EoE) patients at a single-cell transcriptomic level.

2023-08-07 | GSE218607 | GEO

Persistent epithelial barrier dysfunction and Periostin accumulation in histologic remission Eosinophilic Esophagitis

Project description:Patients with Eosinophilic esophagitis (EoE) require long-lasting resolution of inflammation to prevent fibrostenosis and dysphagia. However, the dissociation between symptoms and histologic improvement suggests persistent molecular drivers despite remission. We aimed to characterize persisting molecular alterations in pediatric patients with EoE using tissue proteomics. Esophageal tissue biopsies (n=151) and clinical data were collected prospectively from pediatric patients with EoE (N=34), gastroesophageal reflux disease (GERD; N=10; inflammatory controls) or functional disorders (FD; N=20; non-inflammatory controls). Biospies (n=131) acquired from the diagnostic endoscopy and up to 7 follow-ups were considered for proteome analysis in patients with EoE, while for GERD and FD only biopsies from initial diagnosis were included. Histologically active EoE (15 eosinophils per high power field (hpf)) was diagnosed in 79 biopsies and 52 samples derived from patients with EoE in remission (15 eosinophils per hpf). After microdissection of the epithelium proteins were extracted from the esophageal tissue followed by a liquid chromatography-tandem mass spectrometry. Proteomic analysis identified 3,704 different proteins in total across all samples.

2024-09-23 | PXD052250 | Pride

PolyA RNA-seq from Human esophageal biopsy samples from eosinophilic esophagitis patients

Project description:Analysis of steady-state mRNA levels in 27 samples from healthy controls and patients with fibrostenotic EoE and non-fibrostenotic EoE. Participants range 5 – 18 years old. EoE participants had >15 eosinophils per hpf (eos/hpf) and were classified as fibrostenotic (FS) or non-fibrostenotic (non-fs). FS EoE: having either a) a stricture and/or b) grade 2 or 3 concentric esophageal rings and an esophageal distensibility < 15 mm. Non-fs EoE: no clinical evidence for stricture, circumferential rings or history of food impaction. Included control subjects had no identified abnormalities on endoscopy or histology. Results provide insight into the pathways involved in fibrostenotic remodeling in EoE.

2023-04-08 | GSE197702 | GEO

TaqMan microRNA array of human serum from children with eosinophilic esophagitis

Project description:Serum from children with active and inactive treated eosinophilic esophagitis was analyzed for detection of microRNA Individual serum samples from children with eosinophilic esophagitis were analyzed for detection of microRNA. (n=5 for active EoE and n=5 for inactive EoE)

2014-09-01 | E-GEOD-55793 | biostudies-arrayexpress

Transcriptomic profiling of esophageal epithelium reveals enrichment of IFN-γ response gene signature during active EoE.

Project description:Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophageal mucosa. Although type 2 cytokines are predominant, targeting type 2 inflammation alone is not always effective for all patients. In EoE patients, the transcriptional profiling of esophageal biopsy reveals upregulation of type I and II interferon (IFN) response, dysregulated immune signaling, and downregulation of esophageal-specific genes. However, further investigation is needed to examine the gene expression changes in esophageal epithelium because it plays an important role in EoE. To investigate the upregulation of Interferon Stimulated Genes (ISGs) in EoE esophageal epithelium, we isolated epithelial cells from active EoE patients and non-EoE controls. We performed bulk RNA sequencing to analyze the epithelial-specific transcriptome in EoE. Unsupervised hierarchical clustering of the most variable genes differentiated the active EoE biopsies from non-EoE controls. Gene set enrichment analysis identified IFN-γ response as the most significant upregulated pathway.

2024-02-26 | GSE234973 | GEO

Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13

Project description:To examine the role of the epithelial-derived cytokine, IL-33, in eosinophilic esophagitis (EoE) pathogenesis we developed a novel mouse model (EoE33) in which a secreted and active form of IL-33 is overexpressed by esophageal epithelial cells.

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