Open AccessDifferential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer
Author(s) -
Namba Shinichi,
Sato Kazuhito,
Kojima Shinya,
Ueno Toshihide,
Yamamoto Yoko,
Tanaka Yosuke,
Inoue Satoshi,
Nagae Genta,
Iinuma Hisae,
Hazama Shoichi,
Ishihara Soichiro,
Aburatani Hiroyuki,
Mano Hiroyuki,
Kawazu Masahito
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13937
Subject(s) - promoter , dna methylation , methylation , biology , carcinogenesis , gene silencing , cpg site , genetics , microsatellite instability , epigenetics , epigenetics of physical exercise , cancer research , gene , microbiology and biotechnology , gene expression , microsatellite , allele
The silencing of tumor suppressor genes by promoter CpG island ( CGI ) methylation is an important cause of oncogenesis. Silencing of MLH 1 and BRCA 1 , two examples of oncogenic events, results from promoter CGI methylation. Interestingly, both MLH 1 and BRCA 1 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 Methylation EPIC 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.