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Comprehensive analysis of the transcriptome-wide m6A methylome in colorectal cancer by MeRIP sequencing.

ABSTRACT: Accumulating evidence has demonstrated that N6-methyladenosine (m6A) plays important roles in various cancers, making it essential to profile m6A modifications at a transcriptome-wide scale in colorectal cancer (CRC). In the present study, we performed high-throughput sequencing to determine the m6A methylome in CRC. We obtained six pairs of CRC samples and tumour-adjacent normal tissues from Peking University People's Hospital. We used MeRIP-seq to determine that compared to the tumour-adjacent normal tissues, the CRC samples had 1343 dysregulated m6A peaks, and 625 m6A peaks were significantly upregulated and 718 m6A peaks were significantly downregulated. Genes with altered m6A peaks play critical roles in regulating glucose metabolism, RNA metabolism, and cancer stem cells. Furthermore, we identified 297 hypermethylated m6A peaks and 328 hypomethylated m6A peaks in mRNAs through conjoint analyses of MeRIP-seq and RNA-seq data. After analysing these genes with differentially methylated m6A peaks and synchronously differential expression, we identified four genes (WDR72, SPTBN2, MORC2, and PARM1) that were associated with prognosis of colorectal cancer patients by searching The Cancer Genome Atlas (TCGA). Our study suggests that m6A modifications play important roles in tumour progression and survival of CRC patients. The results also indicate that modulating m6A modifications may represent an alternative strategy to predict the survival of cancer patients and interfere with tumour progression in the future.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7993153 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic mRNAs. There is increasing evidence that m6A plays a key role in tumor progression, so it is important to analyze m6A modifications within the transcriptome-wide in lung adenocarcinoma (LUAD). Three pairs of LUAD samples and tumor-adjacent normal tissues were obtained from the South University of Science and Technology Hospital. And then methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were used to identify differential m6A modifications between tumor and tumor-adjacent normal tissues. We identified 4041 aberrant m6A peaks, of which 1192 m6A peaks were upregulated and 2849 m6A peaks downregulated. It was found that genes with the dysregulated m6A peaks were enriched in the pathways in cancer, Rap1 signaling pathway, and insulin resistance. Additionally, 612 genes with abnormal regulation of m6A peaks and RNA expression were identified by combining MeRIP-seq and RNA-seq data. Through KEGG analysis, the 612 genes were enriched in cancer-related signaling pathways, such as the cGMP-PKG signaling pathway, and the Rap1 signaling pathway. What's more, GSEA enrichment analysis showed these genes were enriched in cell cycle phase transition, cell division, cellular response to DNA damage stimulus, and chromosome organization. To further explore the relationship between differential m6A modified genes and clinical parameters of LUAD patients, we searched The Cancer Genome Atlas (TCGA) and identified 2 genes (FCRL5 and GPRIN1) that were associated with the prognosis and diagnosis of LUAD patients. Furthermore, we found a positive correlation between GPRIN1 and m6A reader YTHDF1 in the GEPIA2 database. It was verified that YTHDF1 binds to GPRIN1 mRNA and regulates its expression. Our study results suggest that m6A modification plays important role in the progression and prognosis of LUAD and maybe a potential new therapeutic target for LUAD patients in the future.

Project description:PurposeTo characterize the entire profile of m6A modifications and differential expression patterns for circRNAs in colorectal cancer (CRC).MethodsFirst, High-throughput MeRIP-sequencing and RNA-sequencing was used to determine the difference in m6A methylome and expression of circRNA between CRC tissues and tumor-adjacent normal control (NC) tissues. Then, GO and KEGG analysis detected pathways involved in differentially methylated and differentially expressed circRNAs (DEGs). The correlations between m6A status and expression level were calculated using a Pearson correlation analysis. Next, the networks of circRNA-miRNA-mRNA were visualized using the Target Scan and miRanda software. Finally, We describe the relationship of distance between the m6A peak and internal ribosome entry site (IRES) and protein coding potential of circRNAs.ResultsA total of 4340 m6A peaks of circRNAs in CRC tissue and 3216 m6A peaks of circRNAs in NC tissues were detected. A total of 2561 m6A circRNAs in CRC tissues and 2129 m6A circRNAs in NC tissues were detected. Pathway analysis detected that differentially methylated and expressed circRNAs were closely related to cancer. The conjoint analysis of MeRIP-seq and RNA-seq data discovered 30 circRNAs with differentially m6A methylated and synchronously differential expression. RT-qPCR showned circRNAs (has_circ_0032821, has_circ_0019079, has_circ_0093688) were upregulated and circRNAs (hsa_circ_0026782, hsa_circ_0108457) were downregulated in CRC. In the ceRNA network, the 10 hyper-up circRNAs were shown to be associated with 19 miRNAs and regulate 16 mRNAs, 14 hypo-down circRNAs were associated with 30 miRNAs and regulated 27 mRNAs. There was no significant correlation between the level of m6A and the expression of circRNAs. The distance between the m6A peak and IRES was not significantly related to the protein coding potential of circRNAs.ConclusionOur study found that there were significant differences in the m6A methylation patterns of circRNAs between CRC and NC tissues. M6A methylation may affect circRNA-miRNA-mRNA co-expression in CRC and further affect the regulation of cancer-related target genes.

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Comprehensive analysis of the transcriptome-wide m6A methylome in colorectal cancer by MeRIP sequencing.

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