Abstract
Changes in genomic DNA methylation patterns are generally assumed to play an important role in the etiology of human cancers. The Dnmt3a enzyme is required for the establishment of normal methylation patterns, and mutations in Dnmt3a have been described in leukemias. Deletion of Dnmt3a in a K-ras–dependent mouse lung cancer model has been shown to promote tumor progression, which suggested that the enzyme might suppress tumor development by stabilizing DNA methylation patterns. We have used whole-genome bisulfite sequencing to comprehensively characterize the methylomes from Dnmt3a wildtype and Dnmt3a-deficient mouse lung tumors. Our results show that profound global methylation changes can occur in K-ras–induced lung cancer. Dnmt3a wild-type tumors were characterized by large hypomethylated domains that correspond to nuclear lamina-associated domains. In contrast, Dnmt3a-deficient tumors showed a uniformly hypomethylated genome. Further data analysis revealed that Dnmt3a is required for efficient maintenance methylation of active chromosome domains and that Dnmt3a-deficient tumors show moderate levels of gene deregulation in these domains. In summary, our results uncover conserved features of cancer methylomes and define the role of Dnmt3a in maintaining DNA methylation patterns in cancer.
Highlights
Altered DNA methylation patterns have long been recognized as important hallmarks of human cancers [1]
Sample selection and characterization Our study is based on a mouse lung cancer model where tumor formation is initiated by conditional activation of an oncogenic Kras allele [19]
Concomitant deletion of Dnmt3a in this model results in significantly more advanced tumors that are characterized by increased size, higher histological grade and papillary growth pattern [18] (Figure 1A and 1B). This experimental system relies on single, defined genetic mutations for tumor initiation and progression, and allows for the dissection of complex cancer-related DNA methylation changes (Figure 1C): (1) Tumor-related changes can be identified through comparisons between normal lung and Dnmt3awt tumors; (2) Dnmt3a-related changes can be identified through comparisons between Dnmt3awt and Dnmt3aKO tumors; (3) methylation patterns of Dnmt3a mutant tumors can be modelled by identifying methylation differences between normal lung and Dnmt3aKO tumors (Figure 1C)
Summary
Altered DNA methylation patterns have long been recognized as important hallmarks of human cancers [1]. DNA methylation patterns are established and maintained by the three DNA methyltransferases Dnmt, Dnmt3a and Dnmt3b [7]. These enzymes have repeatedly been implied in tumor formation, but their precise role in the generation of cancerspecific methylomes is far from understood. It has been shown that heterozygous mutations for Dnmt cause a global reduction in DNA methylation, which was associated with a reduced prevalence of intestinal tumors [8], whereas deletion of Dnmt3b led to reduced tumor size [9]. Consistent with its tumor promoting role, overexpression of Dnmt3b was shown to enhance intestinal tumor formation, which was accompanied by the emergence of methylation patterns that were similar to those usually observed in human colon cancers [10,11]. Genetic mutations in DNMT1 or DNMT3B have not been described in human tumors yet
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