DNA methylation in health and disease: Breast cancer and depression.

摘要

5-methylcytosine is an essential epigenetic mark. To understand the role of aberrant DNA methylation patterns in human disease, we must have a better grasp of wild-type genomic methylation patterns, including the half of the genome comprised of repetitive elements. We have developed a cost-effective, unbiased, whole-genome methylation profiling technique that can assay the methylation state of more than 80% of the CpG sites in the human genome. Using our methylation mapping analysis by paired-end sequencing (Methyl-MAPS) methodology, which couples enzymatic fractionation of DNA by methylation state with next generation sequencing technologies, we determined the methylation profiles of human breast and brain tissue. We found that methylation density increases linearly with CpG density but falls sharply at very high CpG densities. In contrast to single copy sequences, transposons are densely methylated even at very high CpG densities. The presence of histone H2A.Z and histone H3 di- or trimethylated at lysine 4 correlated strongly with unmethylated DNA, primarily at promoter regions. These results indicate that a combination of dinucleotide frequencies, the interaction of repeated sequences, and the presence of histone variants and histone modifications determine the overall shape of genomic methylation patterns.;DNA methylation may play a role in the etiology of neuropsychiatric disorders, possibly through abnormal genomic methylation patterns that regulate genes involved in brain development or physiology. In order to explore the epigenetic profile of major depressive disorder (MDD), we focused on the prefrontal cortex (PFC) due to converging evidence from neuroimaging and functional studies implicating this region in MDD. In the first genome-wide DNA methylation profiling study of major depression, we found that methylation patterns are largely conserved between individuals and brain region, but identified aberrant methylation at several genic and repetitive sequences. These alterations will be the subject of future investigation.;Changes in changes in DNA methylation are a universal finding in cancer, yet questions remain about the mechanisms through which these changes arise and the role of methylation in tumorigenesis. Using our Methyl-MAPS methodology, we profiled two primary tumors. Both tumors had global demethylation across all classes of unique and repetitive sequences. Cell hybrid studies revealed that demethylation in breast cancer cell lines can be a dominant process or maintenance methylation can persist. We propose that changes in methylation in cancer are mediated by a methylation suicide pathway activated in cells that have lost growth control, leading to cell death through apoptotic and inflammatory mechanisms, thereby opposing tumor formation.