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Multi-factor mediated functional modules identify novel classification of ulcerative colitis and functional gene panel.

ABSTRACT: Ulcerative colitis is a chronic, idiopathic, and inflammatory disease of the rectal and colonic mucosa, the behavior of which is of heterogeneity in individuals. Here, we explored the multifactor-mediated functional modules associated with ulcerative colitis classification in the whole genome. Datasets downloaded from the GEO database were used to identify differentially expressed genes between ulcerative colitis patients and healthy individuals initially, followed by acquisition of the remaining ulcerative colitis -related genes from the OMIM and STRING databases. The results identified 914 ulcerative colitis-related genes, of which 60 were differentially expressed genes obtained from GEO datasets. Through weighted co-expression network analysis of ulcerative colitis-related genes, four modules were obtained, three of which were related to ulcerative colitis. Following interactions between microRNA, long noncoding RNA, transcription factors, and module hub genes were predicted and used to construct ulcerative colitis multifactor networks. Additionally, we performed consensus clustering of the ulcerative colitis samples. The results revealed that ulcerative colitis could be divided into four subtypes, with six hub genes identified as potential biomarkers for classification. These findings offer novel insights into ulcerative colitis and a basis for disease classification of ulcerative colitis.

SUBMITTER: Lai L

PROVIDER: S-EPMC7952401 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Multi-factor mediated functional modules identify novel classification of ulcerative colitis and functional gene panel.

Lai Lijie L Li Hanyang H Feng Qi Q Shen Jun J Ran Zhihua Z

Scientific reports 20210311 1

Ulcerative colitis is a chronic, idiopathic, and inflammatory disease of the rectal and colonic mucosa, the behavior of which is of heterogeneity in individuals. Here, we explored the multifactor-mediated functional modules associated with ulcerative colitis classification in the whole genome. Datasets downloaded from the GEO database were used to identify differentially expressed genes between ulcerative colitis patients and healthy individuals initially, followed by acquisition of the remainin ...[more]

PMID: 33707495

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Project description:Background & aimsRecent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC.MethodsColon tissues were collected from patients with UC for bulk RNA sequencing and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing. Genetic association of all protein-altering G-protein coupled receptor single-nucleotide polymorphism was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into Chinese hamster ovary (CHO) and human mast cell (HMC) 1.1 cells to detect genotype-dependent effects on β-arrestin recruitment, IP-1 accumulation, and phosphorylated extracellular signal-regulated kinase.ResultsMast cell-specific mediators and adrenomedullin (proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are up-regulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated with and was bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances β-arrestin recruitment, decreases IP-1, and increases phosphorylated extracellular signal-regulated kinase with MRGPRX2 agonists. Single-cell RNA sequencing defines that adrenomedullin is expressed by activated fibroblasts and epithelial cells and that interferon gamma is a key upstream regulator of mast cell gene expression.ConclusionInflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.

Dataset Information

Multi-factor mediated functional modules identify novel classification of ulcerative colitis and functional gene panel.

Publications

Multi-factor mediated functional modules identify novel classification of ulcerative colitis and functional gene panel.

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