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Comprehensive transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis [miRNA-Seq]

ABSTRACT: BACKGROUND & AIMS: Ulcerative colitis (UC) is an inflammatory bowel disorder with unknown etiology, and given its complex nature, an in vivo model to study its pathophysiology is vital. Animal models play an important role in molecular profiling necessary to pinpoint mechanisms that contribute to human disease. Thus, we aim to identify common conserved gene expression signatures and differentially regulated pathways between human UC and a mouse model hereof, which can be used to identify UC patients from healthy individuals and to suggest novel treatment targets and biomarker candidates. METHODS: Therefore, we performed high-throughput total and small RNA sequencing to comprehensively characterize the transcriptome landscape of the most widely used UC mouse model, the dextran sodium sulfate (DSS) model. We used this data in conjunction with publicly available human UC transcriptome data to compare gene expression profiles and pathways. RESULTS: We identified differentially regulated protein-coding genes, long non-coding RNAs and microRNAs from colon and whole blood of UC mice and further characterized the involved pathways and biological processes through which these genes may contribute to disease development and progression. By integrating human and mouse UC datasets, we suggest a set of 51 differentially regulated genes in UC colon and blood that may improve molecular phenotyping, as well as aid in treatment decisions, drug discovery and the design of clinical trials. CONCLUSION: Global transcriptome analysis of the DSS-UC mouse model supports its use as an efficient high-throughput tool to discover new targets for therapeutic and diagnostic applications in human UC through identifying relationships between gene expression and disease phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE155302 | GEO | 2021/03/13

REPOSITORIES: GEO

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Project description:Inflammation is highly associated with colon carcinogenesis. Epigenetic mechanisms play an important role in the initiation and progression of colon cancer. Curcumin is a dietary cancer preventive phytochemical with promising effect in suppressing colitis-associated colon cancer (CAC) in azoxymethane (AOM) and dextran sulfate sodium (DSS) mouse model. In the present study, we confirmed the effect of curcumin in suppressing colon cancer. Using Agilent SureSelect Methyl-seq and RNA-seq, we obtained single-base methylation profile and transcriptome analyses of epithelial cells from control group, AOM and DSS induced group (AOM+DSS), and AOM and DSS induced plus curcumin treated group (AOM+DSS+Curcumin) in a 18 weeks long-term colon cancer mouse model. We observed differentially expressed genes in pair-wise comparison and identified several pathways of small set of genes involved in the potential preventive effect of curcumin. These pathways include LPS/IL-1 mediated inhibition of RXR function, NRF2-mediated oxidative stress response, aldosterone signaling in epithelial cells, production of NO and ROS in macrophages, and IL-6 signaling. The average DNA methylation levels of the three groups are significantly different also. Based on differential methylation patterns of three groups, several pathways of genes were identified including IL-8 signaling, LPS-stimulated MAPK signaling and colorectal cancer metastasis signaling. Among these methylated pathways and genes, Tnf, an inflammatory gene stood out with decreased DNA CpG methylation in the AOM-DSS as compared to the control group and interestingly curcumin reversed the CpG methylation (validated by pyrosequencing). These observations correlated with decreased, and increased with curcumin, Tnf expression in RNA-seq (validated by qPCR), respectively. The functional role of DNA methylation of Tnf was confirmed by in vitro luciferase transcriptional activity assay. In addition, we found that a group of genes associated with the inflammatory responses and their methylation level was decreased in AOM+DSS group but restored in the curcumin treated group. Taken together, in this study, aberrant DNA CpG methylation of the inflammatory response was found in colitis-associated colon cancer and curcumin restored their CpG methlyation, which could potentially explain the inflammatory and cancer protective effects of curcumin. (Note this GEO/dataset is the RNA-seq part of the study.)

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Comprehensive transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis [miRNA-Seq]

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