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Scientists reveal structure of gateways to gene control

The first complete high-resolution map of structures that control how genes are packaged and regulated throughout an entire genome has been compiled by Penn State scientists. The research suggests how certain nucleosomes control whether a gene's function can be turned on. The study reveals an intimate relationship between the architecture of nucleosomes and the underlying DNA sequences they regulate, including a critical gateway that must be unlocked before a gene can be transcribed.

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Keywords: scientists, reveal, structure, gateways, gene, control, scientist, gateway

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1. Advance in understanding of blood pressure gene could lead to new treatments
   02-04-2007 · EurekAlert!
   Research by scientists at UCL (University College London) has clearly demonstrated for the first time the structure and function of a gene crucial to the regulation of blood pressure. The discovery could be important in the search for new treatments for illnesses such as heart disease, the UK's biggest killer. In a paper published online today in Nature Medicine, the team, led by Professor Patrick Vallance and Dr James Leiper, UCL Department of Medicine, reveal the role of the human gene dimethylarginine dimethylaminohydrolase (DDAH), showing that loss of DDAH activity disrupts nitric oxide (NO) production. NO is critical in the regulation of blood pressure, nervous system functions and the immune system. The role of DDAH is to break down modified amino acids (Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA)) that are produced by the body and have been shown to inhibit NO synthase. These molecules accumulate in various disease states including diabetes, renal failure and pulmonary and systemic hypertension, and their concentration in plasma (the fluid component of blood) is strongly predicative of cardiovascular disease and death. In a healthy human body, the majority of ADMA is eliminated through active metabolism by DDAH. Scientists have hypothesised that if DDAH function is impaired, NO production is reduced, and that this could be an important feature of increased cardiovascular risk. To examine this pathway in more detail, the researchers deleted the DDAH gene in mice. These mice went on to develop hypertension, or high blood pressure. They also designed specific inhibitors (small molecules) which bind to the active site of human DDAH. These small molecule inhibitors also induced hypertension in mice, confirming the importance of DDAH in the regulation of blood pressure. Dr Leiper, UCL Medicine, said: “These genetic and chemical approaches to disrupt DDAH showed remarkably consistent results, and provide compelling evidence that loss of DDAH function increases the concentration of ADMA and thereby disrupts vascular NO signalling. “There has been considerable scientific interest in this pathway and the role of ADMA as a novel risk factor, but so far there's been little evidence to support the idea that it's a cause of disease, rather than just a marker. Genes and their pathways are crucial to our understanding of cardiovascular disease and a better understanding of DDAH-1 could lead to important new treatments. “It could help us to establish if genetic variation predisposes certain people to these diseases, or whether environmental factors exert some of their effects through modulation of DDAH activity. “Our research also shows that this pathway could be harnessed therapeutically to limit production of NO in certain situations where too much nitric oxide is a bad thing; for example, hypotension and septic shock. These are some of the biggest problems in intensive care medicine and there is a huge unmet need for drug treatments.” The study, which was carried out at UCL's Rayne Institute, was funded by grants from the British Heart Foundation, the Wellcome Trust and the Medical Research Council. Professor Jeremy Pearson, Associate Medical Director of the British Heart Foundation, said: "The unexpected finding in the 1980s that a simple gas, nitric oxide (NO), is made by cells in the blood vessel wall and is a powerful control of blood vessel relaxation led to the award of the Nobel Prize in 1998 to its discoverers. "More recently, there has been increasing evidence that impairment of NO production is likely to be an important factor in the development of heart and circulatory disease, but the mechanisms responsible are not fully understood. "This study suggests for the first time that the loss of the activity of the enzyme DDAH-1 leads to reduced NO production and may cause heart and circulatory disease. These findings are likely to be important in the search for new ways to optimise the health of our blood vessels." ### Notes for Editors 1. For more information, please contact Ruth Metcalfe in the UCL Media Relations Office on tel: +44 (0)20 7679 9739, mobile: +44 (0)7990 675 947, out of hours: +44 (0)7917 271 364, e-mail: r.metcalfe@ucl.ac.uk2. 'Disruption of methylarginine metabolism impairs vascular homeostasis' is published in the February issue of the journal Nature Medicine. Advance online publication is embargoed to 18.00 GMT (13.00 US Eastern) Sunday 4 February 2007. Journalists can obtain copies of the paper by contacting the UCL Media Relations Office.3. The study was funded by the British Heart Foundation, the Wellcome Trust and the Medical Research Council. About UCL Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. In the government's most recent Research Assessment Exercise, 59 UCL departments achieved top ratings of 5* and 5, indicating research quality of international excellence. UCL is the fourth-ranked UK university in the 2006 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Mahatma Gandhi (Laws 1889, Indian political and spiritual leader); Jonathan Dimbleby (Philosophy 1969, writer and television presenter); Junichiro Koizumi (Economics 1969, Prime Minister of Japan); Lord Woolf (Laws 1954, Lord Chief Justice of England & Wales); Alexander Graham Bell (Phonetics 1860s, inventor of the telephone), and members of the band Coldplay.
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2. Brown scientists map structure of DNA-doctoring protein complex
   12-06-2006 · EurekAlert!
   Mobile DNA, which inserts foreign genes into target cells, is a powerful force in the march of evolution and the spread of disease. Working with the lambda virus and E. coli bacteria, Brown University biologists have solved the structure of a six-protein complex critical to performing this gene-grafting surgery. The technique they developed could be used to reveal the structure of other critical protein complexes, landing the work on the cover of Molecular Cell.
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3. Gene knockouts reveal FoxOs' vital functions in cancer defense, health of stem cells
   01-25-2007 · EurekAlert!
   In an elegant, multiple-gene knockout experiment, a team of Boston scientists has discovered that a trio of molecules, called FoxOs, are fundamentally critical in preventing some cancers, maintaining blood vessel stability and in keeping blood-forming stem cells healthy.
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4. Inexpensive test detects H5N1 infections quickly and accurately
   11-13-2006 · EurekAlert!
   Scientists from the University of Colorado at Boulder and the Centers for Disease Control and Prevention have developed an inexpensive "gene chip" test based on a single influenza virus gene that could allow scientists to quickly identify flu viruses, including avian influenza H5N1. The MChip may not need to be updated as frequently to keep up with the changing virus.
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5. Feeling hot, hot, hot: New study suggests ways to control fever-induced seizures
   08-21-2007 · EurekAlert!
   Scientists at the University of Toronto Mississauga and Queen's University show that genetic variation in the foraging gene results in different tolerance for heat stress and demonstrate how the use of specific drugs can replicate this effect in fruit flies and locusts. While the findings are at an early stage, the researchers suggest that they could lead to ways to rapidly protect the brain from extremely high fevers in mammals, including humans.
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6. Schizophrenia-linked gene keeps new adult brain cells under control
   09-06-2007 · EurekAlert!
   A gene with reported links to schizophrenia and other mood disorders plays a broader role in the brain than scientists had previously suspected. The study reveals that the gene, known as Disrupted-In-Schizophrenia 1, directs the incorporation of new neurons into the adult brain and keeps the process under control. The gene's newly discovered roles might help to explain why schizophrenia's symptoms generally arise in adolescence or early adulthood, the researchers suggested.
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7. 'Cancer prognosis gene' found to control the fate of breast cells
   11-30-2006 · EurekAlert!
   Scientists have discovered an unsuspected role for a gene known to be one of the best predictors of human breast cancer outcome.
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8. Newly identified mechanism for silencing genes points to possible anti-cancer strategies
   05-16-2007 · EurekAlert!
   Scientists are only beginning to appreciate the extraordinary degree of control exercised over every step of the gene-to-protein production process. Only about 10 percent of human genes, for example, are active in a given cell at a given time, with the remaining 90 percent silenced by a various mechanisms. In a just-published study in Nature, scientists report an important new gene-silencing mechanism that points to promising potential targets for anti-cancer interventions.
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9. University of Washington researchers play leading role in major study of human genome function
   06-13-2007 · EurekAlert!
   Scientists at the University of Washington and other members of an international consortium have completed a multi-year research effort that dramatically boosts understanding of how the human genome functions. While previous studies of the human genome have focused mainly on genes, this study provides insight into non-gene sequences and "regulatory elements" that control genes and may play a role in many common diseases.
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10. From hot springs to rice farms, scientists reveal new insights into the secret lives of archaea
    12-07-2006 · EurekAlert!
    In the world of microbes, as in politics, some groups just can't seem to shake the label ''extremist.'' So it is with archaea, bacteria-like microorganisms whose unique genetics and chemical structure separate them from all other living things.For years, biologists have pigeonholed archaea as extremophiles: creatures that live in extreme conditions. But in the last year, scientists have begun to focus on archaeal species that inhabit more mundane environments, including soils and seawater.
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