Cancer cells genetically engineered to fight their own kind.

Clusters of mutations can mislead researchers.

Circa 2001

DNA methylation is a major epigenetic modification of the genome that regulates crucial aspects of its function. Genomic methylation patterns in somatic differentiated cells are generally stable and heritable. However, in mammals there are at least two developmental periods—in germ cells and in preimplantation embryos—in which methylation patterns are reprogrammed genome wide, generating cells with a broad developmental potential. Epigenetic reprogramming in germ cells is critical for imprinting; reprogramming in early embryos also affects imprinting. Reprogramming is likely to have a crucial role in establishing nuclear totipotency in normal development and in cloned animals, and in the erasure of acquired epigenetic information. A role of reprogramming in stem cell differentiation is also envisaged.

DNA methylation is one of the best-studied epigenetic modifications of DNA in all unicellular and multicellular organisms. In mammals and other vertebrates, methylation occurs predominantly at the symmetrical dinucleotide CpG (1–4). Symmetrical methylation and the discovery of a DNA methyltransferase that prefers a hemimethylated substrate, Dnmt1 , suggested a mechanism by which specific patterns of methylation in the genome could be maintained. Patterns imposed on the genome at defined developmental time points in precursor cells could be maintained by Dnmt1, and would lead to predetermined programs of gene expression during development in descendants of the precursor cells (5, 6). This provided a means to explain how patterns of differentiation could be maintained by populations of cells. In addition, specific demethylation events in differentiated tissues could then lead to further changes in gene expression as needed.

Neat and convincing as this model is, it is still largely unsubstantiated. While effects of methylation on expression of specific genes, particularly imprinted ones and some retrotransposons , have been demonstrated in vivo, it is still unclear whether or not methylation is involved in the control of gene expression during normal development (9–13). Although enzymes have been identified that can methylate DNA de novo (Dnmt3a and Dnmt3b) (14), it is unknown how specific patterns of methylation are established in the genome. Mechanisms for active demethylation have been suggested, but no enzymes have been identified that carry out this function in vivo (15–17). Genomewide alterations in methylation—brought about, for example, by knockouts of the methylase genes—result in embryo lethality or developmental defects, but the basis for abnormal development still remains to be discovered (7, 14).

Yale researchers have discovered how metastasis, the spread of cancer cells throughout the body, is triggered on the molecular level, and have developed a tool with the potential to detect those triggers in patients with certain cancers. The discovery could lead to new ways for treating cancer.

The study was led by Andre Levchenko, the John C. Malone Professor of Biomedical Engineering and director of the Yale Systems Biology Institute at Yale’s West Campus. It was published June 26 in the journal Nature Communications. Levchenko is a member of the Yale Cancer Center.

One way metastasis occurs is through epithelial-mesenchymal transition (EMT), a process that breaks neighboring cells apart from each other and sets them in motion. It’s been long assumed that chemical signals or genetic changes in the cells trigger EMT. But Levchenko’s research team found that it could be caused by a simple change in the texture of the extracellular matrix (ECM), which acts as a scaffold for cells. They discovered that an alignment of the matrix’s fibers (a common biological occurrence) can trigger the EMT process without or other stimuli.