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Mol Cancer Res. 2018 Mar;16(3):461-469. doi: 10.1158/1541-7786.MCR-17-0227. Epub 2018 Jan 12.

Population-dependent Intron Retention and DNA Methylation in Breast Cancer.

Author information

1
Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah.
2
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania.
3
Department of Health and Community Systems, University of Pittsburgh School of Nursing, Pittsburgh, Pennsylvania.
4
Department of Medicine, University of Chicago, Chicago, Illinois.
5
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania. younghee.lee@utah.edu dkim@geisinger.edu.
6
The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania.
7
Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah. younghee.lee@utah.edu dkim@geisinger.edu.
8
Huntsman Cancer Institute, Salt Lake City, Utah.

Abstract

Regulation of gene expression by DNA methylation in gene promoter regions is well studied; however, the effects of methylation in the gene body (exons and introns) on gene expression are comparatively understudied. Recently, hypermethylation has been implicated in the inclusion of alternatively spliced exons; moreover, exon recognition can be enhanced by recruiting the methyl-CpG-binding protein (MeCP2) to hypermethylated sites. This study examines whether the methylation status of an intron is correlated with how frequently the intron is retained during splicing using DNA methylation and RNA sequencing data from breast cancer tissue specimens in The Cancer Genome Atlas. Interestingly, hypomethylation of introns is correlated with higher levels of intron expression in mRNA and the methylation level of an intron is inversely correlated with its retention in mRNA from the gene in which it is located. Furthermore, significant population differences were observed in the methylation level of retained introns. In African-American donors, retained introns were not only less methylated compared to European-American donors, but also were more highly expressed. This underscores the need for understanding epigenetic differences in populations and their correlation with breast cancer is an important step toward achieving personalized cancer care.Implications: This research contributes to the understanding of how epigenetic markers in the gene body communicate with the transcriptional machinery to control transcript diversity and differential biological response to changes in methylation status could underlie some of the known, yet unexplained, disparities in certain breast cancer patient populations. Mol Cancer Res; 16(3); 461-9. ©2018 AACR.

PMID:
29330282
PMCID:
PMC5835176
DOI:
10.1158/1541-7786.MCR-17-0227
[Indexed for MEDLINE]
Free PMC Article

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