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Identification and Validation of Autophagy-Related Genes in Necrotizing Enterocolitis

ABSTRACT: Background: Autophagy plays an essential role in the occurrence and progression of Necrotizing enterocolitis (NEC). We purposed to carry out the identification and validation of the probable autophagy-related genes of NEC via bioinformatics methods and experiment trials. Methods: The autophagy-related differentially expressed genes (arDEGs) of NEC were identified by analyzing the RNA sequencing data of experiment neonatal mouse model and dataset GSE46619. Protein-protein interactions (PPI), gene-ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used for the arDEGs. Then, co-expressed autophagy-related genes in two datasets were identified by Venn analysis and verified by qRT-PCR in experimental NEC. Results: Autophagy increased in experimental NEC and 47 arDEGs were identified in experimental NEC by RNA-sequencing. The PPI results proclaimed those genes interplayed with each other. The GO and KEGG enrichment results of arDEGs reported some certain enriched pathways related to autophagy and macroautophagy. Furthermore, 22 arDEGs were identified in human NEC from dataset GSE46619. The GO and KEGG enrichment analysis of these genes showed similar enriched terms with the results in experimental NEC. Finally, HIF-1a, VEGFA, ITGA3, ITGA6, ITGB4 and NAMPT were identified as co-expressed autophagy-related genes by Venn analysis in human NEC from dataset GSE46619 and experimental NEC. The result of qRT-PCR revealed the expression levels of HIF-1a and ITGA3 upregulated, VEGFA and ITGB4 downregulated in experimental NEC. Conclusion: We identified 47 arDEGs in experimental NEC and 22 arDEGs in human NEC via bioinformatics analysis. HIF-1a, ITGA3, VEGFA and ITGB4 may have effects on the progression of NEC through modulating autophagy.

ORGANISM(S): Mus musculus

PROVIDER: GSE198372 | GEO | 2022/03/11

REPOSITORIES: GEO

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Project description:HIF-1a activates genes under hypoxia and was hypothesized to regulate bone regeneration. Surprisingly, HET HIF-1a fracture calluses are larger, stronger and stiffer than WT HIF-1a calluses due to decreased apoptosis. These data identify apoptosis inhibition as a means to enhance bone regeneration. Introduction: Bone regeneration subsequent to fracture involves the synergistic activation of multiple signaling pathways. Localized hypoxia following fracture activates hypoxia-inducible factor 1 alpha (HIF-1a) leading to increased expression of HIF-1 target genes. We therefore hypothesized that HIF-1a is a key regulator of bone regeneration Materials and Methods: Fixed femoral fractures were generated in mice with partial HIF-1a deficiency (HET HIF-1a) and wild type littermates (WT HIF-1a). Fracture calluses and intact contralateral femurs from post fracture day (PFD) 21 and 28 (N=5-10) were subjected to MicroCT evaluation and 4-point bending in order to assess morphometric and mechanical properties. Molecular analyses were carried out on PFD 7, 10 and 14 samples (N=3) to determine differential gene expression at both mRNA and protein levels. Finally, TUNEL staining was performed on PFD 14 samples (N=2) to elucidate differential apoptosis. Results: Surprisingly, fracture calluses from HET HIF-1a mice exhibit greater mineralization and are larger, stronger and stiffer. Microarray analyses focused on hypoxia-induced genes revealed differential expression (between genotypes) of several genes associated with the apoptotic pathway. Real-time PCR confirmed these results, demonstrating higher expression of pro-apoptotic PP2A and lower expression of anti-apoptotic BCL2 in WT HIF-1a calluses. Subsequent TUNEL staining demonstrates that WT HIF-1a calluses contain larger numbers of TUNEL positive chondrocytes and osteoblasts than HET HIF-1a calluses. Conclusions: We conclude that partial HIF-1a deficiency results in decreased chondrocytic and osteoblastic apoptosis; thereby allowing the development of larger, stiffer calluses and enhancing bone regeneration. Furthermore, apoptosis inhibition may be a promising target for developing new treatments to accelerate bone regeneration. Keywords: Bone, Fracture, Apoptosis, Hypoxia, Microarray

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Identification and Validation of Autophagy-Related Genes in Necrotizing Enterocolitis

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