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Integrating metabolomics and transcriptomics reveals convergent pathways driving radiation-induced salivary gland dysfunction

ABSTRACT: Purpose: The goal of this study is to integrate NGS-derived parotid salivary gland transcriptome profiling (RNA-seq) to metabolomics (UPLC-MS/MS) methods and identify mechanisms driving radiation-induced xerostomia, with potential clinical application to head and neck cancer patients. Methods: Parotid salvary gland mRNA profiles of 28-day-old wild-type (WT) and 5 Gy radiation treated mice were generated by deep sequencing, in triplicate, using Illumina TruSeq. The sequenced reads that passed quality filters were trimmed with Trimmomatic, mapped to mm10 genome with HISAT2, and summarized at the gene level with HTSeq-count and analyzed with DESeq2. Results: Using an optimized data analysis workflow, we mapped sequenced reads per sample to the mouse genome (build mm10) and identified 25422 genes with at least 1 read in the parotid glands of WT and radiation treated mice with HISTA2 workflow. RNA-seq data QA/QC by Principal Component Analysis showed a clear separation between conditions. 155 genes showed significant differential expression between the WT and radiation treated salivary gland, with an adjsuted p-value < 0.05. Pre ranked Gene Set Enrichment Analysis against the CPDB database led to 859 altered pathways with a p-value < 0.05. Integrative analysis pointed to 103 RNA-Seq/Metabolite joint enriched pathways with a p-value < 0.05.

ORGANISM(S): Mus musculus

PROVIDER: GSE155902 | GEO | 2021/03/31

REPOSITORIES: GEO

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Project description:Previous studies suggest that there may be age and gender related differences in salivary gland function. However, the limited and often conflicting information available from healthy populations makes it difficult to confirm these differences. The purpose of the present study was to evaluate and compare changes in gene expression associated with age and gender in the human parotid gland. Differential expression, defined as statistically significant differences with at least 1.5 fold changes, was detected using the AffymetrixÂ® GeneChipÂ® HGU133plus2.0 microarray in 787 gene probe sets; 320 showed higher expression in males, while 467 showed higher expression in females. Several genes associated with saliva secretion were differentially expressed in male and female parotid gland including vesicle-associated membrane protein 3 VAMP3, synaptosomal-associated protein SNAP23, RAS oncogene family member RAB1A, syntaxin binding protein STXBP1. When the gene expression results from the youngest (19-38 years old) and the oldest (65-69 years old) female subjects were further evaluated, it was found that the expression of 228 genes were altered during aging; 155 genes were down-regulated, whereas 73 genes were up-regulated in the female parotid gland. Of the genes that were altered during aging, 24 of the 28 genes (86%) classified as being associated with immune responses were down-regulated in the aged parotid gland. A panel of differentially expressed, age- and gender-related genes was selected for further study by quantitative, real-time RT-PCR. Comparable differences in gene expression were detected by both Affymetrix array and quantitative, real-time RT-PCR methods. Taken together, our data suggest that salivary gland function may be adversely affected in the aged population due, at least in part, to the down regulation of several categories of genes. Moreover, the gender specific gene expressions identified in the present study correlates with the previously observed sexual dimorphism in salivary gland function. Experiment Overall Design: Human parotid glands were obtained from healthy male and female subjects (19-85 years of age). 3 young female parotid glands were compared with 3 older female parotid gland. 8 Female samples were compared with 5 male samples

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Integrating metabolomics and transcriptomics reveals convergent pathways driving radiation-induced salivary gland dysfunction

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