Research Papers:

Distinct epigenetic signatures elucidate enhancer-gene relationships that delineate CIMP and non-CIMP colorectal cancers

Allen Chong _, Jing Xian Teo and Kenneth H.K. Ban

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Oncotarget. 2016; 7:28027-28039. https://doi.org/10.18632/oncotarget.8473

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Allen Chong1,5, Jing Xian Teo2, Kenneth H.K. Ban3,4

1Department of Pathology, National University of Singapore, 119074 Singapore

2Cancer Science Institute, National University of Singapore, 117599 Singapore

3Department of Biochemistry, National University of Singapore, 117596 Singapore

4Institute of Molecular and Cell Biology, 138673 Singapore

5Present address: Shanxi Guoxin Caregeno Medical Laboratories, Taiyuan, Shanxi Province, China

Correspondence to:

Allen Chong, e-mail: [email protected]

Kenneth H.K. Ban, e-mail: [email protected]

Keywords: DNA methylation, enhancers, epigenetics, bioinformatics, colon cancer

Received: December 10, 2015     Accepted: March 14, 2016     Published: March 30, 2016


Epigenetic changes, like DNA methylation, affect gene expression and in colorectal cancer (CRC), a distinct phenotype called the CpG island methylator phenotype (“CIMP”) has significantly higher levels of DNA methylation at so-called “Type C loci” within the genome. We postulate that enhancer-gene pairs are coordinately controlled through DNA methylation in order to regulate the expression of key genes/biomarkers for a particular phenotype.

Firstly, we found 24 experimentally-validated enhancers (VISTA enhancer browser) that contained statistically significant (FDR-adjusted q-value of <0.01) differentially methylated regions (DMRs) (1000bp) in a study of CIMP versus non-CIMP CRCs. Of these, the methylation of 2 enhancers, 1702 and 1944, were found to be very well correlated with the methylation of the genes Wnt3A and IGDCC3, respectively, in two separate and independent datasets.

We show for the first time that there are indeed distinct and dynamic changes in the methylation pattern of specific enhancer-gene pairs in CRCs. Such a coordinated epigenetic event could be indicative of an interaction between (1) enhancer 1702 and Wnt3A and (2) enhancer 1944 and IGDCC3. Moreover, our study shows that the methylation patterns of these 2 enhancer-gene pairs can potentially be used as biomarkers to delineate CIMP from non-CIMP CRCs.

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