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Title: Dnmt3a Protects Active Chromosome Domains against Cancer-Associated Hypomethylation}
Article:
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.
Introduction:
Altered DNA methylation patterns have long been recognized as important hallmarks of human cancers[1]. Over the past 30 years, numerous studies have contributed towards establishing a general model of the cancer methylome and identified a global loss of methylation marks and the hypermethylation of promoter-associated CpG islands as their main features[2]–[4]. Two recent studies have used whole-genome bisulfite sequencing to provide important experimental confirmation for this model[5],[6]: Detailed comparisons between colon cancer and normal colonic mucosa methylomes revealed regions of focal hypermethylation, as well as long stretches of hypomethylated DNA( 100 kb–5 Mb) covering half of the genome. DNA methylation patterns are established and maintained by the three DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b[7]. These enzymes have repeatedly been implied in tumor formation, but their precise role in the generation of cancer-specific methylomes is far from understood. In mouse models, it has been shown that heterozygous mutations for Dnmt1 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]. However, genetic mutations in DNMT1 or DNMT3B have not been described in human tumors yet. DNMT3A is traditionally considered as a de novo DNA methyltransferase that plays an important role in the establishment of methylation patterns during early embryogenesis[12]. Interestingly, recent studies have identified genetic mutations in the human DNMT3A gene in several hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndrome and T-cell lymphoma[13]–[16]. Cancer-associated mutations of DNMT3A are associated with poor prognosis[13]–[15], which suggests that they might functionally contribute to the disease phenotype. However, the described methylation differences between DNMT3A wildtype and mutant patients appear limited[13],[14] and their significance for the disease phenotype has remained unclear. A more detailed methylation analysis was recently described in a mouse model where conditional deletion of Dnmt3a in hematopoietic stem cells caused pronounced differentiation defects in serial transplantation experiments[17]. Further analysis suggested that the absence of Dnmt3a caused both hypermethylation and hypomethylation of promoter regions, and deregulation of stem cell and differentiation genes[17]. Consistent with Dnmt3a acting as a tumor suppressor gene, we have shown that deletion of Dnmt3a promotes tumor progression in a mouse model for lung cancer[18], thus providing a defined experimental system to investigate Dnmt3a-dependent methylome changes in cancer. Immunoprecipitation of methylated DNA suggested that several thousand fragments were hypomethylated in Dnmt3a-deficient tumors. These fragments predominantly localized to intragenic regions, which indicated a preferential activity of Dnmt3a in gene bodies[18]. In an effort to comprehensively and quantitatively characterize Dnmt3a dependent methylation changes at single base-pair resolution we have now used whole-genome bisulfite sequencing to establish genome-wide methylation maps from normal lung tissue, from Dnmt3a wildtype tumors and from Dnmt3a knockout tumors. Our results uncover a novel function of this de novo methyltransferase in cancer, as Dnmt3a deficiency results in loss of methylation in large active chromatin domains.
Discussion:
To date, DNMT3A represents the only DNA methyltransferase gene that has been found to carry genetic mutations in human cancers. The association of DNMT3A mutations with poor prognosis[13]–[15] and the functional effects of DNMT3A mutations on human cells and mouse tumor models[14],[18] suggest that the loss of the enzymatic activity can drive tumorigenesis by inducing tumor-promoting epigenetic lesions. However, human tumors are characterized by a complex pattern of genetic mutations and the specific effects of DNMT3A mutations on the cancer methylome have yet to be identified. In our mouse model, lung tumor formation is initiated by a specific oncogenic mutation, i. e. the activation of the oncogenic K-ras allele in single cells. Dnmt3a is expressed in normal mouse lung tissue and in K-ras dependent mouse lung tumors, and the deletion of Dnmt3a has been shown to promote K-ras dependent lung tumor progression[18]. As such, this system represents a unique model to investigate the cancer-associated methylation changes and to identify the epigenetic alterations that underpin the tumor-promoting effects of Dnmt3a mutations. A previous report provided evidence that conditional deletion of Dnmt3a in hematopoietic stem cells results in both hyper- and hypomethylation of promoters[17]. The observed gain of methylation marks appears difficult to reconcile with the loss of DNA methyltransferase activity, which raises the possibility that the observed methylation differences may be a consequence of the impaired differentiation in Dnmt3a-deficient hematopoietic stem cells. Indeed, our data show an unambiguous loss of methylation marks in Dnmt3a mutant tumors, as expected from a DNA methyltransferase-deficient model. Large domains with reduced levels of DNA methylation have been described as a major feature of human colon cancer methylomes[5],[6]. Our data show that a single oncogenic mutation( a constitutively active mutant K-Ras allele) is sufficient to induce similar hypomethylated domains in mouse lung tumors. While the separation between normally methylated and hypomethylated domains appeared to be less clear than for the human cancer methylomes, this may be related to the experimental design of our analysis that was based on pooled samples to minimize inter-individual variation. Importantly, the hypomethylated domains identified in the tumor samples showed a strong correspondence with lamina-associated domains, which confirms previous observations from human colon cancers[5],[6] and suggests that partially methylated domains( PMDs) represent a conserved feature of tumor methylomes. PMDs are gene-poor, inactive domains and coincide with structural elements in the organization of the genome( lamina-associated domains)[23]. It is possible that PMDs represent genomic regions that have lower functional requirements for faithful methylation maintenance and that maintenance methylation in these domains is generally inefficient. In agreement with this notion, PMDs have also been found to be hypomethylated in cultured normal cell lines[21],[26],[27]. In Dnmt3a-deficient tumors, the methylome became globally hypomethylated. Dnmt3a-mediated protection against global hypomethylation was enriched in large chromosomal domains that showed a complementary distribution to PMDs. These Dnmt3a-protected domains( DPDs) are characterized by a higher overall CpG density and also showed higher levels of H3K4me1, a mark for active regulatory elements. Because of their higher functional significance, these regions might require a more effective mechanism for maintenance methylation. A role for Dnmt3a in effective maintenance methylation has been suggested before[28]–[30], and our study provides detailed insight into this feature. The effects of Dnmt3a-dependent DNA hypomethylation on gene expression appeared to be complex. While we did not find any robust Dnmt3a-dependent methylation changes at promoter regions, we observed a strong enrichment of Dnmt3a-dependent hypomethylation in gene bodies. Interestingly, we found that the hypomethylation of relatively highly methylated 5′-UTRs was associated with higher transcript levels, which might reflect the close proximity of 5′-UTRs to gene promoters, where a silencing function of DNA methylation is well established[31]. We also found that hypomethylation of relatively highly methylated exons was associated with reduced transcript levels, which expands earlier findings[18]. The mechanistic role of exon methylation in gene regulation remains to be analyzed in future studies. It is interesting to note that gene body methylation has been shown to be enriched at splice junctions[32] and to be associated with polymerase II pausing and gene splicing[33]. Altered gene body methylation might thus promote tumor progression through complex quantitative and qualitative alterations in gene expression patterns.
Dnmt3a is generally assumed to be a de novo DNA methyltransferase that plays an important role in establishing DNA methylation patterns during embryogenesis . However , mutations in the human DNMT3A gene have been detected in various cancers , suggesting that the enzyme might also be relevant for DNA methylation in adult tissues and in tumors . We have established genome-wide methylation profiles at single base pair resolution to define Dnmt3a-dependent methylation changes in a mouse tumor model . Our results show that mouse tumors with a functional Dnmt3a enzyme are characterized by regional hypomethylation , while Dnmt3a-deficient tumors showed a uniformly hypomethylated genome . Further data analysis revealed that Dnmt3a is required for maintaining normal DNA methylation patterns specifically in gene bodies and in active chromosome domains . Our study thus defines the role of Dnmt3a in maintaining DNA methylation patterns and provides a paradigm for understanding the effects of DNMT3A mutations on human cancer methylomes .