Distinct Roles for DNMT1 in Modulating the Cancer Epigenome
Embargo until
2019-05-01
Date
2015-11-12
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Johns Hopkins University
Abstract
DNA methylation is an epigenetic modification involved in key physiological processes, including X chromosome inactivation, imprinting, and transcriptional regulation in higher eukaryotes. The methylation patterns are formed early in embryonic development and copied during somatic cell division by a family of enzymes known as DNA methyltransferases (DNMTs). Aberrant DNMT function contributes to hypermethylation of promoter CpG islands in tumor suppressor genes, and hypomethylation of repetitive sequences in the genome. These epigenetic changes play a significant role in various diseases.
While there are three major DNMT isoforms, DNMT1, DNMT3a and DNMT3b, the degree of redundancy of function at specific locations in the genome is not well understood. We have performed genome wide DNA methylation and gene expression analysis using MBD-Seq and RNA-Seq on genomic DNA obtained from a set of isogenic cell lines in which either DNMT1, DNMT3b or both or neither were genetically disrupted. Data from bisulfite sequencing was used to confirm methylation differences between these isogenic lines. These data revealed that while disruption of both DNMT1 and DNMT3b was required to prevent maintenance of methylation at most genomic sites, maintenance of methylation at some genomic regions could be abrogated by disruption of just DNMT1 or DNMT3b. We found that while DNMT3b is concentrated in coding exons, DNMT1 localizes to putative promoter regions. Additionally, DNMT1’s methylating ability is independent of clonal selection, and DNMT1 mediated methylation leads to gene repression in a subset of genomic regions. Finally, we discovered that DNMT1 could also control gene expression in the absence of DNA methylation, acting as a transcriptional repressor for a subset of genes.
Identifying DNMT1’s methylation dependent and independent roles in gene silencing is an important aspect of translational research. We hope our data will to provide a clearer understanding of DNMT1’s role in tumorigenesis, leading to identification of new disease models and chemotherapeutic targets.
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Keywords
DNMT1, DNA methylation