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Differential Expression Profiles and Functional Prediction of circRNAs in Necrotizing Enterocolitis.

ABSTRACT: Circular RNAs (circRNAs), a novel type of noncoding RNAs, have been demonstrated to behave as microRNA (miRNA) sponges to exert their effects during pathological processes of diseases. However, the roles of circRNAs have not been explored in necrotizing enterocolitis (NEC). This study sought to identify differentially expressed circRNAs and predict their potential biological functions in NEC. circRNA expression profiles in terminal ileum from newborn rats with NEC and normal controls were explored using next-generation sequencing. In the NEC group, 53 circRNAs were significantly differentially expressed, including 9 upregulated and 44 downregulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted, and circRNA-miRNA interaction networks were generated to predict the potential roles of circRNAs in NEC progression. Further investigation revealed that most circRNAs include miRNA binding sites and that some are implicated in NEC development. In conclusion, this study's findings demonstrate that differentially expressed circRNAs are involved in NEC development via their interactions with miRNAs, making them prospective targets for NEC diagnosis and treatment.

SUBMITTER: Pan Y

PROVIDER: S-EPMC8581514 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Differential Expression Profiles and Functional Prediction of circRNAs in Necrotizing Enterocolitis.

Pan Ya Y Chen Wenjuan W Yan Xiangyun X Yu Boshi B Yao Shuwen S Chen Xiaohui X Han Shuping S

BioMed research international 20211103

Circular RNAs (circRNAs), a novel type of noncoding RNAs, have been demonstrated to behave as microRNA (miRNA) sponges to exert their effects during pathological processes of diseases. However, the roles of circRNAs have not been explored in necrotizing enterocolitis (NEC). This study sought to identify differentially expressed circRNAs and predict their potential biological functions in NEC. circRNA expression profiles in terminal ileum from newborn rats with NEC and normal controls were explor ...[more]

PMID: 34778461

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Project description:BackgroundTraumatic heterotopic ossification (HO) is an intractable sequela incited by inflammatory insult. To date, the exact molecular mechanisms of traumatic HO formation remain unclear. Recent studies have indicated that circular RNAs (circRNAs) participate in various human skeletal diseases. Although the formation of HO recapitulates many programs during bone development and remodeling, few data are available concerning whether circRNAs could participate in this pathological osteogenesis.MethodsTo investigate the differentially expressed circRNAs (DE-circRNAs) in HO formation, microarray assay was performed to analyze the circRNA expression profile in four pairs of mice HO tissues and normal tissues. Then, qRT-PCR was applied to verify the microarray data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed the biological functions of the differentially expressed circRNAs target genes. Cytoscape software was used to construct the circRNA-miRNA-mRNA network for circRNAs with different expression levels as well as the target genes.ResultsWe demonstrated that 491 circRNAs were significantly differentially expressed in mouse HO tissues by a fold-change ≥ 2 and p-value ≤ 0.05. Among them, the expressions of 168 circRNAs were increased, while 323 were decreased. The expression levels of 10 selected circRNAs were verified successfully by qRT-PCR. GO analysis exhibited that these DE-circRNAs participated in a series of cellular processes. KEGG pathway analysis revealed that multiple upregulated and downregulated pathways were closely related to the DE-circRNAs in HO mice. The circRNA-miRNA-mRNA networks demonstrated that DE-circRNAs may be involved in the pathological osteogenesis of HO through the circRNA-targeted miRNA-mRNA axis.ConclusionOur study first demonstrated the expression profiles and predicted the potential functions of DE-circRNAs in mice traumatic HO, which may shed new light on the elucidation of mechanisms as well as provide novel potential peripheral biological diagnostic markers and therapeutic targets for traumatic HO.

Project description:Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are the most common acute surgical emergencies associated with high morbidity and mortality in preterm infants. We aimed to compare the profiles of immunoregulatory proteins and identify novel mediators in plasma of NEC and SIP infants. We also investigated the expression of target genes in resected intestinal tissues and an enterocyte cell line. Using Cytokine Antibody Array assay, we reported the first comparative profiles of immunoregulatory proteins in plasma of NEC and SIP infants, and showed that dysregulated proteins belonged to functionally diversified categories, including pro- and anti-inflammation, angiogenesis, cell growth, wound healing, anti-apoptosis, cell adhesion and extracellular matrix reorganization. Validation by ELISA confirmed significantly higher concentrations of interleukin (IL)-6, angiopoietin (Ang)-2, soluble type II interleukin-1 receptor (sIL-1RII), and soluble urokinase-type plasminogen activator receptor (suPAR) in NEC infants compared with gestational age-matched control, and a lower level of an epidermal growth factor receptor, secreted form of receptor tyrosine-protein kinase ErbB3 (sErbB3), compared with SIP infants. mRNA expressions of IL1-RII and uPAR were up-regulated in resected bowel tissues from NEC infants, indicating that immunoregulation also occurred at the cellular level. In FHs-74 Int cells, Ang-2, IL1-RII and uPAR mRNA expressions were significantly induced by the combined treatment with lipopolysaccharide (LPS) and platelet activating factor (PAF). Our study provided plasmatic signatures of immunoregulatory proteins in NEC and SIP infants, and demonstrated involvement of multiple functional pathways. The magnitude of changes in these proteins was significantly more extensive in NEC infants, reflecting the different nature of injury and/or severity of inflammation. We speculate that dysregulation of IL-6, Ang-2, IL-1RII and uPAR occurred at both systemic and cellular levels, and probably mediated via LPS and endogeneous PAF signals. Such exaggerated immunologic responses may account for the high morbidity and mortality in NEC compared with SIP patients.

Project description:BackgroundNecrotizing enterocolitis (NEC) is a common, potentially catastrophic intestinal disease among very low birthweight premature infants. Affecting up to 15% of neonates born weighing less than 1500 g, NEC causes sudden-onset, progressive intestinal inflammation and necrosis, which can lead to significant bowel loss, multi-organ injury, or death. No unifying cause of NEC has been identified, nor is there any reliable biomarker that indicates an individual patient's risk of the disease. Without a way to predict NEC in advance, the current medical strategy involves close clinical monitoring in an effort to treat babies with NEC as quickly as possible before irrecoverable intestinal damage occurs. In this report, we describe a novel machine learning application for generating dynamic, individualized NEC risk scores based on intestinal microbiota data, which can be determined from sequencing bacterial DNA from otherwise discarded infant stool. A central insight that differentiates our work from past efforts was the recognition that disease prediction from stool microbiota represents a specific subtype of machine learning problem known as multiple instance learning (MIL).ResultsWe used a neural network-based MIL architecture, which we tested on independent datasets from two cohorts encompassing 3595 stool samples from 261 at-risk infants. Our report also introduces a new concept called the "growing bag" analysis, which applies MIL over time, allowing incorporation of past data into each new risk calculation. This approach allowed early, accurate NEC prediction, with a mean sensitivity of 86% and specificity of 90%. True-positive NEC predictions occurred an average of 8 days before disease onset. We also demonstrate that an attention-gated mechanism incorporated into our MIL algorithm permits interpretation of NEC risk, identifying several bacterial taxa that past work has associated with NEC, and potentially pointing the way toward new hypotheses about NEC pathogenesis. Our system is flexible, accepting microbiota data generated from targeted 16S or "shotgun" whole-genome DNA sequencing. It performs well in the setting of common, potentially confounding preterm neonatal clinical events such as perinatal cardiopulmonary depression, antibiotic administration, feeding disruptions, or transitions between breast feeding and formula.ConclusionsWe have developed and validated a robust MIL-based system for NEC prediction from harmlessly collected premature infant stool. While this system was developed for NEC prediction, our MIL approach may also be applicable to other diseases characterized by changes in the human microbiota.

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Differential Expression Profiles and Functional Prediction of circRNAs in Necrotizing Enterocolitis.

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Differential Expression Profiles and Functional Prediction of circRNAs in Necrotizing Enterocolitis.

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