Abstract
BackgroundDNA methylation is a key epigenetic mark in mammalian organisms that plays key roles in chromatin organization and gene expression. Although DNA methylation in gene promoters is generally associated with gene repression, recent studies demonstrate that DNA methylation in gene bodies and intergenic regions of the genome may result in distinct modes of gene regulation. Furthermore, the molecular mechanisms underlying the establishment and maintenance of DNA methylation in human health and disease remain to be fully elucidated. We recently demonstrated that a subset of long non-coding RNAs (lncRNAs) associates with the major DNA methyltransferase DNMT1 in human colon cancer cells, and the dysregulation of such lncRNAs contribute to aberrant DNA methylation patterns.ResultsIn the current study, we assessed the impact of a key DNMT1-associated lncRNA, DACOR1, on genome-wide DNA methylation using reduced representation bisulfite sequencing (RRBS). Our findings demonstrated that induction of DACOR1 in colon cancer cells restores DNA methylation at thousands of CpG sites throughout the genome including promoters, gene bodies, and intergenic regions. Importantly, these sites overlap with regions of the genome that become hypomethylated in colon tumors. Furthermore, induction of DACOR1 results in repression of FOS and JUN and, consequently, reduced AP-1 transcription factor activity.ConclusionCollectively, our results demonstrate a key role of lncRNAs in regulating DNA methylation in human cells, and the dysregulation of such lncRNAs could emerge as a key mechanism by which DNA methylation patterns become altered in human tumors.
Highlights
DNA methylation is a key epigenetic mark in mammalian organisms that plays key roles in chromatin organization and gene expression
In a recent publication from our laboratory, we demonstrated that many long non-coding RNAs are associated with DNA methyltransferase 1 (DNMT1), suggesting that long non-coding RNAs have important functions in regulating genome-wide DNA methylation [14]
We further demonstrated that one such Long non-coding RNA (lncRNA), DNMT1-associated colon cancer repressed lncRNA 1 (DACOR1), is a positive regulator of DNA methylation in cell culture models of the disease
Summary
DNA methylation is a key epigenetic mark in mammalian organisms that plays key roles in chromatin organization and gene expression. The epigenetic code is comprised of specific patterns of histone and DNA modifications [1,2,3], which cooperate to control gene expression without changing the underlying DNA sequence, typically through recruitment of various protein complexes to alter chromatin accessibility [4]. There is global dysregulation of the epigenetic landscape in cancer cells, as compared to matched normal cells [4, 6–9] These massive epigenetic alterations are thought to be critical events in the initiation and progression of tumorigenesis, and act in cooperation with somatic gene mutations to mediate tumor progression. Despite these extensive epigenetic changes in many tumor types, the underlying molecular mechanisms driving epigenetic changes are still emerging, as they are not always driven by mutations in key epigenetic modifiers [4,5,6, 9, 10]
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