Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer.
CpG Islands
DNA methylation
colorectal neoplasms
microsatellite instability
oligonucleotide array sequence analysis
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Mar 2019
Mar 2019
Historique:
received:
16
10
2018
revised:
26
12
2018
accepted:
28
12
2018
pubmed:
15
1
2019
medline:
9
3
2019
entrez:
15
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30637877
doi: 10.1111/cas.13937
pmc: PMC6398885
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1096-1104Subventions
Organisme : Japan Agency for Medical Research and Development
ID : JP17am0001001
Organisme : Japan Agency for Medical Research and Development
ID : JP17cm0106502
Organisme : Japan Society for the Promotion of Science
ID : 16K07143
Organisme : Japan Society for the Promotion of Science
ID : 17J00386
Informations de copyright
© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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