First analysis of tumor-suppressor interactions with whole genome in normal human cells reveals key differences with cancer cells

ScienceDaily (Nov. 30, 2011) — Scientists investigating the interactions, or binding patterns, of a major tumor-suppressor protein known as p53 with the entire genome in normal human cells have turned up key differences from those observed in cancer cells. The distinct binding patterns reflect differences in the chromatin (the way DNA is packed with proteins), which may be important for understanding the function of the tumor suppressor protein in cancer cells.

The study was conducted by scientists at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory and collaborators at Cold Spring Harbor Laboratory, and is published in the December 15 issue of the journal Cell Cycle.

"No other study has shown such a dramatic difference in a tumor suppressor protein binding to DNA between normal and cancer-derived cells," said Brookhaven biologist Krassimira Botcheva, lead author on the paper. "This research makes it clear that it is essential to study p53 functions in both types of cells in the context of chromatin to gain a correct understanding of how p53 tumor suppression is affected by global epigenetic changes -- modifications to DNA or chromatin -- associated with cancer development."

Because of its key role in tumor suppression, p53 is the most studied human protein. It modulates a cell's response to a variety of stresses (nutrient starvation, oxygen level changes, DNA damage caused by chemicals or radiation) by binding to DNA and regulating the expression of an extensive network of genes. Depending on the level of DNA damage, it can activate DNA repair, stop the cells from multiplying, or cause them to self-destruct -- all of which can potentially prevent or stop tumor development. Malfunctioning p53 is a hallmark of human cancers.

Most early studies of p53 binding explored its interactions with isolated individual genes, and all whole-genome studies to date have been conducted in cancer-derived cells. This is the first study to present a high-resolution genome-wide p53-binding map for normal human cells, and to correlate those findings with the "epigenetic landscape" of the genome.

"We analyzed the p53 binding in the context of the human epigenome, by correlating the p53 binding profile we obtained in normal human cells with a published high-resolution map of DNA methylation -- a type of chemical modification that is one of the most important epigenetic modifications to DNA -- that had been generated for the same cells," Botcheva said.

Key findings

In the normal human cells, the scientists found p53 binding sites located in close proximity to genes and particularly at the sites in the genome, known as transcriptions start sites, which represent "start" signals for transcribing the genes. Though this association of binding sites with genes and transcription start sites was previously observed in studies of functional, individually analyzed binding sites, it was not seen in high-throughput whole-genome studies of cancer-derived cell lines. In those earlier studies, the identified p53 binding sites were found not close to genes, and not close to the sites in the human genome where transcription starts.

Additionally, nearly half of the newly identified p53 binding sites in the normal cells (in contrast to about five percent of the sites reported in cancer cells) reside in so-called CpG islands. These are short DNA sequences with unusually high numbers of cytosine and guanine bases (the C and G of the four-letter genetic code alphabet, consisting of A, T, C, and G). CpG islands tend to be hypo- (or under-) methylated relative to the heavily methylated mammalian genome.

"This association of binding sites with CpG islands in the normal cells is what prompted us to investigate a possible genome-wide correlation between the identified sites and the CpG methylation status," Botcheva said.

The scientists found that p53 binding sites were enriched at hypomethylated regions of the human genome, both in and outside CpG islands.

"This is an important finding because, during cancer development, many CpG islands are subjected to extensive methylation while the bulk of the genomic DNA becomes hypomethylated," Botcheva said. "These major epigenetic changes may contribute to the differences observed in the p53-binding-sites' distribution in normal and cancer cells."

The scientists say this study clearly illustrates that the genomic landscape -- the DNA modifications and the associated chromatin changes -- have a significant effect on p53 binding. Furthermore, it greatly extends the list of experimentally defined p53 binding sites and provides a general framework for investigating the interplay between transcription factor binding, tumor suppression, and epigenetic changes associated with cancer development.

This research, which was funded by the DOE Office of Science, lays groundwork for further advancing the detailed understanding of radiation effects, including low-dose radiation effects, on the human genome.

The research team also includes John Dunn and Carl Anderson of Brookhaven Lab, and Richard McCombie of Cold Spring Harbor Laboratory, where the high-throughput Illumina sequencing was done.

Methodology

The p53 binding sites were identified by a method called ChIP-seq: for chromatin immunoprecipitation (ChIP), which produces a library of DNA fragments bound by a protein of interest using immunochemistry tools, followed by massively parallel DNA sequencing (seq) for determining simultaneously millions of sequences (the order of the nucleotide bases A, T, C and G in DNA) for these fragments.

"The experiment is challenging, the data require independent experimental validation and extensive bioinformatics analysis, but it is indispensable for high-throughput genomic analyses," Botcheva said. Establishing such capability at BNL is directly related to the efforts for development of profiling technologies for evaluating the role of epigenetic modifications in modulating low-dose ionizing radiation responses and also applicable for plant epigenetic studies.

The analysis required custom-designed software developed by Brookhaven bioinformatics specialist Sean McCorkle.

"Mapping the locations of nearly 20 million sequences in the 3-billion-base human genome, identifying binding sites, and performing comparative analysis with other data sets required new programming approaches as well as parallel processing on many CPUs," McCorkle said. "The sheer volume of this data required extensive computing, a situation expected to become increasingly commonplace in biology. While this work was a sequence data-processing milestone for Brookhaven, we expect data volumes only to increase in the future, and the computing challenges to continue."

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Journal References:

Krassimira Botcheva, Sean R. McCorkle, W.R. McCombie, John J. Dunn, Carl W. Anderson. Distinct p53 genomic binding patterns in normal and cancer-derived human cells. Cell Cycle, 2011; 10 (24) [link]William A. Freed-Pastor, Carol Prives. Dissimilar DNA binding by p53 in normal and tumor-derived cells. Cell Cycle, 2011; 10 (24) [link]

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Scientists use laser imaging to assess safety of zinc oxide nanoparticles in sunscreen

ScienceDaily (Nov. 30, 2011) — Ultra-tiny zinc oxide (ZnO) particles with dimensions less than one-ten-millionth of a meter are among the ingredients list of some commercially available sunscreen products, raising concerns about whether the particles may be absorbed beneath the outer layer of skin. To help answer these safety questions, an international team of scientists from Australia and Switzerland have developed a way to optically test the concentration of ZnO nanoparticles at different skin depths. They found that the nanoparticles did not penetrate beneath the outermost layer of cells when applied to patches of excised skin.

The results, which were published this month in the Optical Society's (OSA) open-access journal Biomedical Optics Express, lay the groundwork for future studies in live patients.

The high optical absorption of ZnO nanoparticles in the UVA and UVB range, along with their transparency in the visible spectrum when mixed into lotions, makes them appealing candidates for inclusion in sunscreen cosmetics. However, the particles have been shown to be toxic to certain types of cells within the body, making it important to study the nanoparticles' fate after being applied to the skin. By characterizing the optical properties of ZnO nanoparticles, the Australian and Swiss research team found a way to quantitatively assess how far the nanoparticles might migrate into skin.

The team used a technique called nonlinear optical microscopy, which illuminates the sample with short pulses of laser light and measures a return signal. Initial results show that ZnO nanoparticles from a formulation that had been rubbed into skin patches for 5 minutes, incubated at body temperature for 8 hours, and then washed off, did not penetrate beneath the stratum corneum, or topmost layer of the skin. The new optical characterization should be a useful tool for future non-invasive in vivo studies, the researchers write.

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Zhen Song, Timothy A. Kelf, Washington H. Sanchez, Michael S. Roberts, Jaro Ricka, Martin Frenz, Andrei V. Zvyagin. Characterization of optical properties of ZnO nanoparticles for quantitative imaging of transdermal transport. Biomedical Optics Express, 2011; 2 (12): 3321 DOI: 10.1364/BOE.2.003321

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A revolutionary new 'dry ink' for laser printers and photocopy machines

ScienceDaily (Nov. 30, 2011) — Imagine someone inventing a "super-toner," a revolutionary new "dry ink" for copiers and laser printers that produces higher-quality, sharper color images more economically, cutting electricity by up to 30 percent. One that also reduces emissions of carbon dioxide -- the main greenhouse gas -- in the production of tens of thousands of tons of toner produced each year. One that reduces the cost of laser printing, making it more affordable in more offices, schools and homes.

Sound like a toner that is too good to be true? Well, a team of scientists at the Xerox Corporation actually invented it. A new episode in the 2011 edition of a  video series from the American Chemical Society (ACS), the world's largest scientific society, focuses on the research and the teamwork that led to this advance.

Titled Prized Science: How the Science Behind ACS Awards Impacts Your Life, the videos are available without charge at the Prized Science website and on DVD.

ACS encourages educators, schools, museums, science centers, news organizations and others to embed links to Prized Science on their websites. The videos discuss scientific research in non-technical language for general audiences. New episodes in the series, which focuses on ACS' 2011 award recipients, will be issued in November and December.

"Science awards shine light on individuals who have made impressive achievements in research," noted ACS President Nancy B. Jackson, Ph.D. "Often, the focus is on the recipients, with the public not fully grasping how the award-winning research improves the everyday lives of people around the world. The Prized Science videos strive to give people with no special scientific knowledge the chance to discover the chemistry behind the American Chemical Society's national awards and see how it improves and transforms our daily lives."

A Revolutionary New "Dry Ink" for Laser Printers & Photocopy Machines features the research of Patricia Burns, Ph.D., Grazyna Kmiecik-Lawrynowicz, Ph.D., Chieh-Min Cheng, Ph.D., and Tie Hwee Ng, Ph.D., winners of the 2011 ACS Award for Team Innovation sponsored by the ACS Corporation Associates. Toner is the fine powder used instead of ink in photocopy machines, laser printers and multifunction devices -- machines that print, copy and fax. The researchers at Xerox developed a new toner called "EA Toner," which stands for "emulsion aggregation." They start with a liquid material that looks like house paint. That's the "emulsion" part. Then, they throw in pigments for color, waxes and other useful things and let everything "aggregate," or stick together. Then, it all dries out, and what's left is a fine powder that they can put into a toner cartridge. That worked fine in the lab, but scaling it up to produce millions of toner cartridges to meet consumers' demands was difficult -- all of the scientists had to work together to make the new toner a commercial reality.

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Gene is first linked to herpes-related cold sores

ScienceDaily (Nov. 30, 2011) — A team of researchers from the University of Utah and the University of Massachusetts has identified the first gene associated with frequent herpes-related cold sores.

The findings were published in the Dec. 1, 2011, issue of the Journal of Infectious Diseases.

Herpes simplex labialis (HSL) is an infection caused by herpes simplex virus type 1 (HSV-1) that affects more than 70 percent of the U.S. population. Once HSV-1 has infected the body, it is never removed by the immune system. Instead, it is transported to nerve cell bodies, where it lies dormant until it is reactivated. The most common visible symptom of HSV-1 reactivation is a cold sore on or around the mouth. Although a majority people are infected by HSV-1, the frequency of cold sore outbreaks is extremely variable and the causes of reactivation are uncertain.

"Researchers believe that three factors contribute to HSV-1 reactivation -- the virus itself, exposure to environmental factors, and genetic susceptibility," says John D. Kriesel, M.D., research associate professor of infectious diseases at the University of Utah School of Medicine and first author on the study. "The goal of our investigation was to define genes linked to cold sore frequency."

Kriesel and his colleagues previously had identified a region of chromosome 21 containing six genes significantly linked to HSL disease using DNA collected from 43 large families to map the human genome. In the current study, Kriesel and his colleagues performed intensive analysis of this chromosome region using single nucleotide polymorphism (SNP) genotyping, a test which identifies differences in genetic make-up between individuals.

"Using SNP genotyping, we were able to identify 45 DNA sequence variations among 618 study participants, 355 of whom were known to be infected with HSV-1," says Kriesel. "We then used two methods called linkage analysis and transmission disequilibrium testing to determine if there was a genetic association between particular DNA sequence variations and the likelihood of having frequent cold sore outbreaks."

Kriesel and his colleagues discovered that an obscure gene called C21orf91 was associated with susceptibility to HSL. They identified five major variations of C21orf91, two of which seemed to protect against HSV-1 reactivation and two of which seemed to increase the likelihood of having frequent cold sore outbreaks.

"There is no cure for HSV-1 and, at this time, there is no way for us to predict or prevent cold sore outbreaks," says Kriesel. "The C21orf91 gene seems to play a role in cold sore susceptibility, and if this data is confirmed among a larger, unrelated population, this discovery could have important implications for the development of drugs that affect cold sore frequency."

Kriesel's University of Utah collaborators include Maurine R. Hobbs, Ph.D., research assistant professor of internal medicine and adjunct assistant professor of human genetics, and Mark F. Leppert, Ph.D., distinguished professor and former chair of human genetics.

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J. D. Kriesel, B. B. Jones, N. Matsunami, M. K. Patel, C. A. St. Pierre, E. A. Kurt-Jones, R. W. Finberg, M. Leppert, M. R. Hobbs. C21orf91 Genotypes Correlate With Herpes Simplex Labialis (Cold Sore) Frequency: Description of a Cold Sore Susceptibility Gene. Journal of Infectious Diseases, 2011; 204 (11): 1654 DOI: 10.1093/infdis/jir633

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Petroleum-eating mushrooms

ScienceDaily (Nov. 30, 2011) — Take a Petri dish containing crude petroleum and it will release a strong odor distinctive of the toxins that make up the fossil fuel. Sprinkle mushroom spores over the Petri dish and let it sit for two weeks in an incubator, and surprise, the petroleum and its smell will disappear. "The mushrooms consumed the petroleum!" says Mohamed Hijri, a professor of biological sciences and researcher at the University of Montreal's Institut de recherche en biologie végétale (IRBV).

Hijri co-directs a project with B. Franz Lang promoting nature as the number one ally in the fight against contamination. Lang holds the Canada Research Chair on Comparative and Evolutionary Genomics and is a professor at the university's Department of Biochemistry. By using bacteria to stimulate the exceptional growth capacity of certain plants and microscopic mushrooms, Hijri and Lang believe they are able to create in situ decontamination units able to successfully attack the most contaminated sites on the planet.

The recipe is simple. In the spring, we plant willow cuttings at 25-centimeter intervals so the roots dive into the ground and soak up the degrading contaminants in the timber along with the bacteria. At the end of the season, we burn the stems and leaves and we are left with a handful of ashes imprisoning all of the heavy metals that accumulated in the plant cells. Highly contaminated soil will be cleansed after just a few cycles. "In addition, it's beautiful," says Hijri pointing to a picture of dense vegetation covering the ground of an old refinery after just three weeks.

Thanks to the collaboration of an oil company from the Montreal area, the researchers had access to a microbiological paradise: an area where practically nothing can grow and where no one ventures without protective gear worthy of a space traveler. This is where Hijri collected microorganisms specialized in the ingestion of fossil fuels. "If we leave nature to itself, even the most contaminated sites will find some sort of balance thanks to the colonization by bacteria and mushrooms. But by isolating the most efficient species in this biological battle, we can gain a lot of time."

Natural and artificial selection

This is the visible part of the project, which could lead to a breakthrough in soil decontamination. The project is called Improving Bioremediation of Polluted Soils Through Environmental Genomics and it requires time-consuming sampling and fieldwork as well as DNA sequencing of the species in question. The project involves 16 researchers from the University of Montreal and McGill University, many of which are affiliated with the IRBV. The team also includes four researchers, lawyers and political scientists, specializing in the ethical, environmental, economic, legal and social aspects of genomics.

The principle is based on a well-known process in the sector called phytoremediation that consists in using plant matter for decontamination. "However, in contaminated soils, it isn't the plant doing most of the work," says Lang. "It's the microorganisms i.e. the mushrooms and bacteria accompanying the root. There are thousands of species of microorganisms and our job is to find the best plant-mushroom-bacteria combinations."

Botanist Michel Labrecque is overseeing the plant portion of the project. The willow seems to be one of the leading species at this point given its rapid growth and premature foliation. In addition, its stem grows even stronger once it has been cut. Therefore, there is no need to plant new trees every year. However, the best willow species still needs to be determined.

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Engineered botulism toxins could have broader role in medicine

ScienceDaily (Nov. 30, 2011) — The most poisonous substance on Earth -- already used medically in small doses to treat certain nerve disorders and facial wrinkles -- could be re-engineered for an expanded role in helping millions of people with rheumatoid arthritis, asthma, psoriasis and other diseases, scientists are reporting. Their study appears in ACS' journal Biochemistry.

Edwin Chapman and colleagues explain that toxins, or poisons, produced by Clostridium botulinum bacteria, cause of a rare but severe form of food poisoning, are the most powerful toxins known to science. Doctors can inject small doses, however, to block the release of the neurotransmitters, or chemical messengers, that transmit signals from one nerve cell to another. The toxins break down a protein in nerve cells that mediates the release of neurotransmitters, disrupting nerve signals that cause pain, muscle spasms and other symptoms in certain diseases. That protein exists not just in nerve cells, but in other cells in the human body. However, these non-nerve cells lack the receptors needed for the botulinum toxins to enter and work. Chapman's group sought to expand the potential use of the botulinum toxins by hooking it to a molecule that can attach to receptors on other cells.

Their laboratory experiments showed that these engineered botulinum toxins do work in non-nerve cells, blocking the release of a protein from immune cells linked to inflammation, which is the underlying driving force behind a range of diseases. Such botulinum toxin therapy holds potential in a range of chronic inflammatory diseases and perhaps other conditions, which could expand the role of these materials in medicine.

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Felix L. Yeh, Yiming Zhu, William H. Tepp, Eric A. Johnson, Paul J. Bertics, Edwin R. Chapman. Retargeted Clostridial Neurotoxins as Novel Agents for Treating Chronic Diseases. Biochemistry, 2011; 50 (48): 10419 DOI: 10.1021/bi201490t

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Two out of three medical students do not know when to wash their hands

ScienceDaily (Dec. 1, 2011) — Only 21 percent of surveyed medical students could identify five true and two false indications of when and when not to wash their hands in the clinical setting, according to a study published in the December issue of the American Journal of Infection Control, the official publication of APIC -- the Association for Professionals in Infection Control and Epidemiology.

Three researchers from the Institute for Medical Microbiology and Hospital Epidemiology at Hannover Medical School in Hannover, Germany collected surveys from 85 medical students in their third year of study during a lecture class that all students must pass before bedside training and contact with patients commences. Students were given seven scenarios, of which five ("before contact to a patient," "before preparation of intravenous fluids," "after removal of gloves," "after contact to the patient's bed," and "after contact to vomit") were correct hand hygiene (HH) indications. Only 33 percent of the students correctly identified all five true indications, and only 21 percent correctly identified all true and false indications.

Additionally, the students expected that their own HH compliance would be "good" while that of nurses would be lower, despite other published data that show a significantly higher rate of HH compliance among nursing students than among medical students. The surveyed students further believed that HH compliance rates would be inversely proportional to the level of training and career attainment of the physician, which confirms a previously discovered bias among medical students that is of particular concern, as these higher-level physicians are often the ones training the medical students at the bedside.

"There is no doubt that we need to improve the overall attitude toward the use of alcohol-based hand rub in hospitals," conclude the authors. "To achieve this goal, the adequate behavior of so-called 'role models' is of particular importance."

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The above story is reprinted from materials provided by Elsevier, via AlphaGalileo.

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K. Graf and I.F. Chaberny, R.-P. Vonberg. Beliefs about hand hygiene: A survey in medical students in their first clinical year. American Journal of Infection Control, Volume 39, Issue 10 (December 2011)

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