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Archive - Mar 23, 2011

Zebrafish Model Reveals New Gene for Human Melanoma

Looking at the dark stripes on the tiny zebrafish you might not expect that they hold a potentially important clue for discovering a treatment for the deadly skin disease melanoma. Yet melanocytes, the same cells that are responsible for the pigmentation of zebrafish stripes and for human skin color, are also where melanoma originates. Dr. Craig Ceol, assistant professor of molecular medicine at the University of Massachusetts Medical School, and collaborators at several institutions, used zebrafish to identify a new gene responsible for promoting melanoma. In a paper featured on the cover of the March 24 issue of Nature, Dr. Ceol and colleagues describe the melanoma-promoting gene SETDB1, which codes for a methyl transferase. "We've known for some time that there are a number of genes that are responsible for the promotion and growth of melanoma," said Dr. Ceol, who completed the research while a postdoctoral fellow in the lab of Howard Hughes Medical Institute investigator Dr. Leonard Zon at Children's Hospital Boston. "With existing methods, it had been difficult to identify what those genes are. By developing the new approach described in this paper, we were able to isolate SETDB1 as one of those genes." Cases of melanoma, an aggressive form of skin cancer, have been on the rise in the United States: in 2009 alone, 68,000 new cases were diagnosed and 8,700 people died of the disease. Though it accounts for less than 5 percent of all skin cancers, it is responsible for the majority of deaths from skin cancers and has a poor prognosis when diagnosed in its advanced stages. Early signs of melanoma include changes to the shape or color of existing moles or the appearance of a new lump anywhere on the skin.

Epigenomic Findings Have Implications for Common Disease Studies

Genes make up only a tiny percentage of the human genome. The rest, which has remained measurable but mysterious, may hold vital clues about the genetic origins of disease. Using a new mapping strategy, a collaborative team led by researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and MIT has begun to assign meaning to the regions beyond our genes and has revealed how minute changes in these regions might be connected to common diseases. The researchers' findings appeared online on March 23, 2011 in Nature. The results have implications for interpreting genome-wide association studies (GWAS) – large-scale studies of hundreds or thousands of people in which scientists look across the genome for single "letter" changes or SNPs (single nucleotide polymorphisms) that influence the risk of developing a particular disease. The majority of SNPs associated with disease reside outside of genes and, until now, very little was known about the functions of most of them. "Our ultimate goal is to figure out how our genome dictates our biology," said co-senior author Dr. Manolis Kellis, a Broad associate member and associate professor of computer science at MIT. "But 98.5 percent of the genome is non-protein coding, and those non-coding regions are generally devoid of annotation." The term "epigenome" refers to a layer of chemical information on top of the genetic code, which helps determine when and where (and in what types of cells) genes will be active. This layer of information consists of chemical modifications, or "chromatin marks," that appear across the genetic landscape of every cell, and can differ dramatically between cell types.

Trigger Found for Autoimmune Heart Attacks

People with autoimmune type 1 diabetes, whose insulin-producing cells have been destroyed by the body's own immune system, are particularly vulnerable to a form of inflammatory heart disease (myocarditis) caused by a different autoimmune reaction. Scientists at the Joslin Diabetes Center have now revealed the exact target of this other onslaught, taking a large step toward potential diagnostic and therapeutic tools for the heart condition. Researchers in the lab of Dr. Myra Lipes, have shown in both mice and people that myocarditis can be triggered by a protein called alpha-myosin heavy chain, which is found only in heart muscle and in especially low quantities in human heart tissue. While myocarditis often follows viral attacks or other infections, Dr. Lipes and her colleagues previously demonstrated that mice genetically modified to model type 1 diabetes could generate myocarditis spontaneously. In their latest work, reported online on March 23, 2011, in the Journal of Clinical Investigation, the scientists analyzed blood from such mice and identified two types of autoimmune response directed specifically against the protein, with the first response directed by a specialized kind of immune system cells called T cells and the second by antibodies. In both mice and people, T cells are "trained" by specialized cells in the thymus, a small organ in front of the heart, to recognize the body's own cells and refrain from attacking them. The researchers found, however, that in mice these specialized training cells couldn't train on the alpha-myosin heavy chain protein because none of that protein was being produced in those cells. Next, the scientists showed that the disease didn't develop in similar mice that were genetically engineered to produce the protein in the specialized training cells.

Mechanism of Zeta Toxin Bacterial Suicide Explained

The zeta toxins are a family of proteins that are normally present within various pathogenic bacteria and can mysteriously trigger suicide when the cells undergo stress. A team led by Dr. Anton Meinhart at the Max Planck Institute for Medical Research in Heidelberg has now found the mechanism underlying this programmed bacterial cell death. The team’s paper, published in PLoS Biology, reports that zeta toxins convert a compound required for bacterial cell wall synthesis into a poison that kills bacteria from within. In the future, it may be possible to hijack this mechanism for defense against bacteria and to design drugs that mimic these toxins. Most bacteria harbor toxin-antitoxin (TA) systems, in which a bacterial toxin lies dormant under normal conditions, prevented from being active by its antitoxin counterpart. As long as the antitoxin is present, the bacterium can continue to exist and is not affected by the TA system. Under conditions of stress, however, the antitoxin is degraded, freeing the toxin to attack its host from within. Although the family of zeta toxins was discovered almost 20 years ago, their deadly mechanism has been enigmatic until now. The first author on the paper, Dr. Hannes Mutschler, and his colleagues studied the molecular mechanism of action of the zeta toxin PezT from the PezAT (Pneumococcal epsilon zeta Antitoxin Toxin) system using the model bacterium Escherichia coli. The PezAT system is found in the major human pathogen Streptococcus pneumoniae - a bacterium that causes serious infections such as pneumonia, septicemia, and meningitis. Bacterial cells in which PezT was activated showed symptoms of poisoning similar to the effects of penicillin. This involved first stalling in the middle of their division stage, and later the intersection zone between the two cell bodies burst and the cells died.