Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer

Abstract

The silencing of tumor suppressor genes by promoter CpG island (CGI) methylation is an important cause of oncogenesis. Silencing of MLH1 and BRCA1, two examples of oncogenic events, results from promoter CGI methylation. Interestingly, both MLH1 and BRCA1 have a divergent promoter, from which another gene on the opposite strand is also transcribed. Although studies have shown that divergent transcription is an important factor in transcriptional regulation, little is known about its implication in aberrant promoter methylation in cancer. In this study, we analyzed the methylation status of CGI in divergent promoters using a recently enriched transcriptome database. We measured the extent of CGI methylation in 119 colorectal cancer (CRC) clinical samples (65 microsatellite instability high [MSI‐H] CRC with CGI methylator phenotype, 28 MSI‐H CRC without CGI methylator phenotype and 26 microsatellite stable CRC) and 21 normal colorectal tissues using Infinium MethylationEPIC BeadChip. We found that CGI within divergent promoters are less frequently methylated than CGI within unidirectional promoters in normal cells. In the genome of CRC cells, CGI within unidirectional promoters are more vulnerable to aberrant methylation than CGI within divergent promoters. In addition, we identified three DNA sequence motifs that correlate with methylated CGI. We also showed that methylated CGI are associated with genes whose expression is low in normal cells. Thus, we here provide fundamental observations regarding the methylation of divergent promoters that are essential for the understanding of carcinogenesis and development of cancer prevention strategies.

Genome-Wide Analysis of Cell-Free DNA Methylation Profiling for the Early Diagnosis of Pancreatic Cancer

“…Lay et al (2015) demonstrated that compared to non-CGI promoters, methylation in CGI promoters had a greater impact on nucleosome phasing and histone modifications which have an influence on directing the functional organization of cancer epigenome. Tumorigenesis often coincides with CGI hypermethylation, leading to the inactivation of tumor suppressor genes (Namba et al, 2019). In a study of the genome-wide search for identifying potentially methylated changes during the progression of colorectal neoplasia, (Gu et al, 2019) found that hypermethylation occurred mainly in the overlap regions of CGIs and promoters, while hypomethylation tended to be far away from functional regions.…”

MSIMEP: Predicting microsatellite instability from microarray DNA methylation tumor profiles

“…MSI status and clinical characteristics were provided by the corresponding author upon request ( Table S2 E). 33 …”

The Progress of the Specific and Rapid Genetic Detection Methods for Ovarian Cancer Diagnosis and Treatment

“…The detection of related mutated genes provides a significant reference for ovarian cancer genetic risk assessment, early screening, and prognosis assessment. In addition to genetic mutations encoding structural proteins, non-coding RNAs (ncRNAs) 3 and epigenetic changes 4 also provide us with a wealth of genetic information in the era of precision medicine. Therefore, genetic testing provides essential guidance for ovarian cancer screening, staging, and prognosis evaluation.…”