Epigenetics of Hematopoiesis, Stem Cell Reprogramming, and Cancer

Since the discovery of altered DNA methylation in cancer in 1982, most studies of cancer epigenetics have focused on epimutations which could serve as surrogates of mutation. In the past decade, we and our collaborators have been leading efforts to develop whole-genome approaches to epigenetic analysis of human disease, that include novel approaches to array-based analysis and whole-genome bisulfite sequencing. This has led to the first whole-genome bisulfite sequencing methylation map of the cancer genome. Surprising results have been the discovery of CpG island shores and large hypomethylated blocks corresponding to nuclear lamina/heterochromatin regions, and accounting for the vast majority of epigenetic alterations in cancer. These results point to the possibility that at least solid tumors represent epigenetically a single process with a common molecular characteristic; namely increased epigenetic plasticity that allows selection of the tumor cells at the expense of the host. This view can explain most of the hallmarks of cancer, as well as offering a strategy for powerful new approaches to risk detection and treatment. This whole-genome epigenetic approach has also revealed that the classical lineage structure of hematopoiesis is very well reflected in DNA methylation, but that there are very surprising dynamic changes in this process, with waves of both increasing and decreasing methylation changes. This work has also revealed a molecular basis for phenotypic memory in induced pluripotent stem cells, as well as a strong connection between reprogramming differentially methylated regions, or R-DMRs, and tissue-specific differentially methylated regions, or T-DMRs.