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Translational Medicine transient, low-level expression of stem cell factors. "In ongoing studies, we have additionally shown the possibility of generating pancreatic cells and hepatocytes by direct reprogramming," he says. Heterogeneity Persists "There is long-term value in developing strategies to deliver cells as medicines," says George Q. Daley, M.D., Ph.D, professor of hematology and oncology at Children's Hospital Boston. Signifcant research efforts in Dr. Daley's group are focusing on developing blood stem cells for clinical applications. He and his colleagues recently revealed that the highly conserved Notch signaling pathway, previously implicated in several hematopoietic conditions, plays a critical role in the early stages of hematopoiesis in human embryonic and induced pluripotent stem cells (iPSCs), a fnding that is opening new avenues toward understanding hematopoietic fate specifcation. Particularly for blood cell diseases with a known genetic basis, cell-based therapies are emerging as a promising option, but safety considerations—due in part to possible immune responses—are a limiting factor. The use of iPSCs, in which the genetic defect is corrected, may circumvent this concern. However, an insuffciently understood phenomenon in cellular reprogramming revolves around the notion that not all iPSCs are identical. Signifcant functional variability, defned as differences between embryonic stem cells and iPSCs, as well as clone-to-clone heterogeneity were found, and appear to be shaped by a combination of genetic and epigenetic contributions. "It is perplexing how unpredictable some stem cells are, and we do not yet have a good understanding of this phenomenon," Dr. Daley says. Stem cell variability and heterogeneity appear to be more accentuated for certain cell types and pose major roadblocks in implementing clinical applications. Dr. Daley and his colleagues are focusing on translating a technology to generate platelets of suffcient robustness for stem cell-based therapies. "We are trying to determine how many cell lines we need to generate, to reasonably expect to fnd one with the desirable performance properties, and this has to be balanced against the extremely high costs," he says. Complex Perturbations "About a decade ago, Rafael Irizarry [Ph.D.] and I developed a genomic arraybased method to look in an unbiased way at methylation over a region encompassing a large fraction of the methylome," says Andrew P. Feinberg, M.D., professor of molecular medicine at Johns Hopkins University School of Medicine. Taking this approach, known as comprehensive high-throughput array-based relative methylation, the researchers revealed that most tissue-specifc DNA methylation differences, which historically were thought to be confned at CpG islands, are in fact situated at regions within approximately two kilobases from their boundaries, in the so-called CpG island shores. Whole-genome bisulfde sequencing showed that the sharp demarcation between the high methylation found at CpG islands and the lower methylation found at CpG island shores is lost in cancer, and the shift of the boundaries toward the CpG islands or away from them results in aberrant methylation patterns. An additional stride toward understanding genome-wide DNA methylation in disease came about when, in a comparison between colorectal cancer and normal colorectal mucosa from the same patients, the researchers identifed large chromosomal blocks of DNA, extending over approximately half the genome, that become hypomethylated in cancer. Largely corresponding to structures known as LOCKs (large organized chroma- tin lysine modifcation regions), these regions also show an approximately 80% overlap with lamin-associated domains, which were found microscopically and are thought to be associated with the nuclear membrane. These genomic regions, which correspond to heterochromatin and are highly methylated in normal cells, increase in size during differentiation and are lost in cancer. 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