Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes

Adam Blattler, Lijing Yao, Heather Witt, Yu Guo, Charles M. Nicolet, Benjamin P. Berman, Peggy J. Farnham

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

BACKGROUND: Gene expression is epigenetically regulated by a combination of histone modifications and methylation of CpG dinucleotides in promoters. In normal cells, CpG-rich promoters are typically unmethylated, marked with histone modifications such as H3K4me3, and are highly active. During neoplastic transformation, CpG dinucleotides of CG-rich promoters become aberrantly methylated, corresponding with the removal of active histone modifications and transcriptional silencing. Outside of promoter regions, distal enhancers play a major role in the cell type-specific regulation of gene expression. Enhancers, which function by bringing activating complexes to promoters through chromosomal looping, are also modulated by a combination of DNA methylation and histone modifications.

RESULTS: Here we use HCT116 colorectal cancer cells with and without mutations in DNA methyltransferases, the latter of which results in a 95% reduction in global DNA methylation levels. These cells are used to study the relationship between DNA methylation, histone modifications, and gene expression. We find that the loss of DNA methylation is not sufficient to reactivate most of the silenced promoters. In contrast, the removal of DNA methylation results in the activation of a large number of enhancer regions as determined by the acquisition of active histone marks.

CONCLUSIONS: Although the transcriptome is largely unaffected by the loss of DNA methylation, we identify two distinct mechanisms resulting in the upregulation of distinct sets of genes. One is a direct result of DNA methylation loss at a set of promoter regions and the other is due to the presence of new intragenic enhancers.

Original languageEnglish (US)
Pages (from-to)469
Number of pages1
JournalGenome Biology
Volume15
Issue number9
DOIs
StatePublished - 2014
Externally publishedYes

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Histone Code
methylation
DNA methylation
DNA Methylation
gene expression
histones
promoter regions
Gene Expression
DNA
Genetic Promoter Regions
gene expression regulation
methyltransferases
Methyltransferases
Gene Expression Regulation
cells
loss
colorectal neoplasms
Transcriptome
transcriptome
Methylation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Blattler, A., Yao, L., Witt, H., Guo, Y., Nicolet, C. M., Berman, B. P., & Farnham, P. J. (2014). Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes. Genome Biology, 15(9), 469. https://doi.org/10.1186/s13059-014-0469-0

Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes. / Blattler, Adam; Yao, Lijing; Witt, Heather; Guo, Yu; Nicolet, Charles M.; Berman, Benjamin P.; Farnham, Peggy J.

In: Genome Biology, Vol. 15, No. 9, 2014, p. 469.

Research output: Contribution to journalArticle

Blattler, A, Yao, L, Witt, H, Guo, Y, Nicolet, CM, Berman, BP & Farnham, PJ 2014, 'Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes', Genome Biology, vol. 15, no. 9, pp. 469. https://doi.org/10.1186/s13059-014-0469-0
Blattler, Adam ; Yao, Lijing ; Witt, Heather ; Guo, Yu ; Nicolet, Charles M. ; Berman, Benjamin P. ; Farnham, Peggy J. / Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes. In: Genome Biology. 2014 ; Vol. 15, No. 9. pp. 469.
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