Scientists complete first mapping of molecule found in human embryonic stem cells

ScienceDaily (July 21, 2011) — Stem cell researchers at UCLA have generated the first genome-wide mapping of a DNA modification called 5-hydroxymethylcytosine (5hmC) in embryonic stem cells, and discovered that it is predominantly found in genes that are turned on, or active.See Also:Health & MedicineGenesStem CellsHuman BiologyBrain TumorProstate CancerLymphomaReferenceBRCA1Tumor suppressor geneEmbryonic stem cellDNA microarray

The finding by researchers with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA may prove to be important in controlling diseases like cancer, where the regulation of certain genes plays a role in disease development.

"Any way you can control genes will be hugely important for human disease and cancer," said Steven E. Jacobsen, a professor of molecular, cell and developmental biology in the Life Sciences and a Howard Hughes Medical Institute investigator. "Cancer is generally a problem of genes being inappropriately turned off or mutated, like tumor suppressors genes, or genes that should be off getting switched on."

The study appears in the July issue of the journal Genome Biology.

5hmC is formed from the DNA base cytosine by adding a methyl group and then a hydroxy group. The molecule is important in epigenetics -- the study of changes in gene expression caused by mechanisms other than changes in the DNA sequence -- because the newly formed hydroxymethyl group on the cytosine can potentially switch a gene on and off, Jacobsen said.

The molecule 5hmC was only recently discovered, and its function has not been clearly understood, Jacobsen said. Until now, researchers didn't know where 5hmC was located within the genome.

"That is important to know because it helps you to understand how it is functioning and what it's being used for," said Jacobsen, who also is a researcher with UCLA's Jonsson Comprehensive Cancer Center. "We had known that DNA could be modified by 5hmC, but it wasn't clear where on the genome this was occurring."

Jacobsen, whose lab studies the molecular genetics and genomics of DNA methylation patterning, used genomics to define where in human embryonic stem cells the 5hmC was present. They used human embryonic stem cells because it had been shown previously that the molecule is abundant in those cells, as well as in brain cells, Jacobsen said.

In the study, Jacobsen found that 5hmC was associated with genes and tended to be found on genes that were active. The study also revealed that 5hmC was present on a type of DNA regulatory element, called enhancers, which help control gene expression. In particular, 5hmC was present on enhancers that are crucial for defining the nature of the human embryonic stem cells.

The results suggest that 5hmC plays a role in the activation of genes. This is opposite of the role of the more well studied 5mC (DNA methylation), which is involved in silencing genes. This relationship is in line with the view that 5hmC is created directly from 5mC.

"If we can understand the function of 5hmC, that will lead to greater understanding of how genes are turned on and off and that could lead to the development of methods for controlling gene regulation," Jacobsen said.

Moving forward, Jacobsen and his team will seek to uncover the mechanism by which 5hmC is created from DNA methylation and how it becomes localized to particular areas of the genome, such as the enhancers.

The two-year study was funded by the Howard Hughes Medical Institute, a Fred Eiserling and Judith Lengyel Graduate Doctoral Fellowship, the Leukemia & Lymphoma Society, the National Institutes of Health and by an Innovation Award from the Eli and Edythe Broad Center of Regenerative Medicine & Stem Cell Research at UCLA.

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A novel and potent antioxidant found in tomato plants, initial results suggest

ScienceDaily (July 22, 2011) — A team of researchers from the Institute of Molecular and Cell Biology (IBMCP) -a joint centre of the Universitat Politècnica de València and CSIC, the Spanish National Research Council- have identified a novel and potent natural antioxidant occurring in tomato plants. It is a phenolic substance that is synthesised by the tomato plant when it is subjected to biotic stress. Until now, it was completely unknown.See Also:Health & MedicineVitamin CVitamin EPlants & AnimalsEndangered PlantsBotanyEarth & ClimateEnvironmental PolicyGrasslandReferencePolyphenol antioxidantMediterranean dietAntioxidantEssential nutrient

The UPV and CSIC have registered the national and international patents of the new antioxidant and the laboratory procedures used to isolate and synthesise it chemically.

The finding was recently published in the journal Environmental and Experimental Botany.

IBMCP researchers point out that the antioxidant power of the new compound is much higher -14 times higher, to be precise- than, for example, that of resveratrol, a well-known antioxidant, found in red wine, which can delay cellular aging. In addition, it is 4.5 times more potent than vitamin E and 10 times more potent than vitamin C.

This substance could have multiple applications. For example, in the food industry it could be used as a preservative in food for human consumption and in animal fodder, because of its action as a retarder of lipid oxidation. This powerful antioxidant would prevent changes such as fats and oils becoming rancid, which strongly diminishes food quality. It could also be used as a supplement in certain products after careful processing.

Cancer-causing mineral found in U.S. road gravel: Erionite in roads may increase risk of mesothelioma

ScienceDaily (July 25, 2011) — As school buses drive down the gravel roads in Dunn County, North Dakota, they stir up more than dirt. The clouds of dust left in their wake contain such high levels of the mineral erionite that those who breathe in the air every day are at an increased risk of developing mesothelioma, a type of cancer of the membranes around the lungs, new research shows. Erionite is a natural mineral fiber that shares similar physical similarities with asbestos. When it's disturbed by human activity, fibers can become airborne and lodge themselves in people's lungs. Over time, the embedded fibers can make cells of the lung grow abnormally, leading to mesothelioma, a form of lung cancer most often associated with the related mineral asbestos.See Also:Health & MedicineMesotheliomaLung CancerDiseases and ConditionsMatter & EnergyWeapons TechnologyFossil FuelsEnergy PolicyReferenceAsbestosMesotheliomaCarcinogenIndoor air quality

Michele Carbone, M.D., Ph.D., director of the University of Hawaii Cancer Center in Honolulu, has previously linked erionite exposure in some Turkish villages to unusually high rates of mesothelioma. Recently, he and colleagues turned their attention to potential erionite exposure in the U.S., where at least 12 states have erionite-containing rock deposits. His research team -- which includes scientists from the National Institute of Environmental Health Sciences, Environmental Protection Agency, New York University, University of Chicago, University of Iowa, and University of Hacettepe -- focused their efforts on Dunn County, North Dakota, when they learned that rocks containing erionite have been used to produce gravel for the past 30 years. More than 300 miles of roads are now paved with the gravel.

The new study, reported in the July 25, 2011 issue of Proceedings of the National Academy of Sciences (PNAS) is the first to look at the potential hazards associated with erionite exposure in the U.S.

The scientists compared the erionite in North Dakota to erionite from the Turkish villages with high mesothelioma rates. They measured airborne concentrations of the mineral in various settings, studied its chemical composition, and analyzed its biological activity. When mice were injected with the erionite from Dunn County, their lungs showed signs of inflammation and abnormal cell growth, precursors to mesothelioma. Under the microscope, the fiber size of the erionite from North Dakota was similar to that of the Turkish erionite. Overall, the researchers found no chemical differences between the North Dakota erionite and samples of the cancer-causing mineral from Turkey. The airborne levels of erionite in North Dakota were comparable to levels found in Turkish villages with 6-8 percent mortality rates from mesothelioma, the researchers reported.

"Based on the similarity between the erionite from the two sources," says Carbone, "there is concern for increased risk of mesothelioma in North Dakota." The long latency period of the disease -- it can take 30 to 60 years of exposure to cause mesothelioma -- and the fact that many erionite deposits have only been mined in the past few decades suggests that the number of cases could soon be on the rise. In addition to North Dakota, California, Oregon, Arizona, Nevada and other states have erionite deposit, but the possibility of human exposure elsewhere in the U.S. has not yet been investigated.

In contrast to asbestos, which causes mesothelioma at lower rates, there are no established health benchmarks in the U.S. on safe levels of erionite exposure, because until recently, physicians thought that erionate was present only in Turkey. The new findings, however, indicate that precautionary measures should be put in place to reduce exposure to the mineral, says Carbone. In Turkey, his earlier findings led to moving villagers away from areas with high levels of erionite, into new housing built out of erionite-free materials. "Our findings provide an opportunity to implement novel preventive and detection programs in the U.S. similar to what we have been doing in Turkey," he says. Future studies could analyze erionite levels in other areas of the U.S. and develop strategies to prevent and screen for mesothelioma. The study was funded through grants from the National Cancer Institute and the 2008 AACR-Landon Innovator Award for International Collaboration in Cancer Research to Michele Carbone.

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New target found for nitric oxide's attack on salmonella bacteria

ScienceDaily (July 23, 2011) — A new target for nitric oxide has been revealed in studies of how it inhibits the growth of Salmonella. This bacterium is a common cause of food-poisoning.See Also:Health & MedicineFoodborne IllnessInfectious DiseasesDentistryPlants & AnimalsBacteriaExtreme SurvivalMicrobiologyReferenceNitrogen oxideSoil lifeCatalysisNitrous oxide

"Nitric oxide is naturally produced in the nose and the gut and other tissues in the body to ward off infection," explained the senior author of the paper, Dr. Ferric Fang. He is a University of Washington (UW) professor of laboratory medicine, microbiology and medicine.

Nitric oxide -- not to be confused with nitrous oxide, the laughing gas in dentists' offices -- is similar to the preservatives in hotdogs, Fang said. Reactive nitrogen species, like nitric oxide, make brown meat an appetizing pink. They also weed out microorganisms that spoil food or cause food poisoning.

Fang's lab has made several important discoveries on ways mammals exploit the biochemical properties of nitric oxide to defend themselves from germs. Nitric oxide, a key actor in the body's innate immune defenses, apprehends a rogue's gallery of disease-causing organisms.

The newest results underscore that nitric oxide's antimicrobial actions are due to its interference with the metabolism, or energy production, of pathogens.

"Nitric oxide imposes substantial metabolic restrictions on bacteria," the researchers noted. Fang explained that its reactions with numerous metabolic targets accounts for the broad-spectrum nature of its success. It keeps many types of disease-causing bacteria at bay. It also prevents an overgrowth of the body's many helpful bacteria.

The latest report on the versatility of nitric oxide in arming hosts against pathogens is published in the July 21 issue of Cell Host & Microbe. Dr. Anthony R. Richardson, who is now at the University of North Carolina at Chapel Hill, led the research while he was a postdoctoral fellow in the Fang lab.

Fang's team looked at the multi-pronged action of nitric oxide on Salmonella enterica serovar Typhimurium. This type of Salmonella can contaminate food and is similar to the bacteria that cause typhoid fever.

Nitric oxide and related chemicals put Salmonella into a difficult situation called nitrosative stress. When exposed to nitric oxide, Salmonella is unable to make two essential amino acids, methionine and lysine.

Without these, Salmonella cannot grow.

"This is bad news for the bacteria, but not for the host," Fang said. "Nitric oxide doesn't damage the host that produces it."

The ability to withstand nitrosative stress makes some forms of bacteria more virulent than milder types that can't handle it.

Richardson and his colleagues found that nitric oxide and its cousins throw a monkey wrench into several points in the Krebs cycle, also known as the tricarboxylic acid cycle. This cycle is the second stage in cellular respiration, when fuel is broken down to release energy for cell growth and division.

The researchers outlined how multiple interruptions in this cycle create a series of biochemical consequences that starve Salmonella of methionine and lysine. Nitric oxide also blocks certain regulatory genes that otherwise would give Salmonella an alternate chemical route out of its distress.

"Collectively, this work demonstrates that nitric oxide imposes substantial metabolic restrictions on bacteria," the authors concluded.

In a commentary on these findings, Dr. Stephen Spiro of the Department of Molecular and Cell Biology at the University of Texas at Dallas wrote that the work "focuses renewed interest in central metabolic pathways as nitric oxide targets."

"More generally," he noted, "this study provides an excellent illustration that a proper understanding of host-pathogen interactions and the development of therapeutic interventions require a detailed knowledge of pathogen metabolism."

Nitric oxide's targeting of the Krebs cycle is not unique to Salmonella. In learning how the body naturally controls the energy supplies and growth of varied disease-causing organisms, Fang said, scientists may be able to develop new broad-spectrum antimicrobials that mimic these effects, drugs that promote the body's own natural defenses against infection, or agents that overcome the ways virulent bacteria compensate when being starved of certain nutrients.

The research was supported by grants from the National Institutes of Health.

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