BEYOND DNA: EPIGENETICS PLAYS LARGE ROLE IN BLOOD FORMATION
From FMS Global News Desk of Jeanne Hambleton Released: 11-Aug-2014
Source: Weizmann Institute of Science – Science, August 7, 2014
Newswise — Blood stem cells have the potential to turn into any type of blood cell, whether it be the oxygen-carrying red blood cells, or the immune system’s many types of white blood cells that help fight infection. How exactly is the fate of these stem cells regulated? Preliminary findings from research conducted by scientists from the Weizmann Institute of Science and the Hebrew University are starting to reshape the conventional understanding of the way blood stem cell fate decisions are controlled, thanks to a new technique for epigenetic analysis they have developed. Understanding epigenetic mechanisms (environmental influences other than genetics) of cell fate could lead to the deciphering of the molecular mechanisms of many diseases, including immunological disorders, anemia, leukemia, and many more. It also lends strong support to findings that environmental factors and lifestyle play a more prominent role in shaping our destiny than previously realized.
The process of differentiation – in which a stem cell becomes a specialized mature cell – is controlled by a cascade of events in which specific genes are turned “on” and “off” in a highly regulated and accurate order. The instructions for this process are contained within the DNA itself in short regulatory sequences. These regulatory regions are normally in a “closed” state, masked by special proteins called histones to ensure against unwarranted activation. Therefore, to access and “activate” the instructions, this DNA mask needs to be “opened” by epigenetic modifications of the histones so it can be read by the necessary machinery.
In a paper published in Science, Dr. Ido Amit and David Lara-Astiaso of the Weizmann Institute’s Department of Immunology, along with Prof. Nir Friedman and Assaf Weiner of the Hebrew University of Jerusalem, charted – for the first time – histone dynamics during blood development. Thanks to the new technique for epigenetic profiling they developed, in which just a handful of cells – as few as 500 – can be sampled and analyzed accurately, they have identified the exact DNA sequences, as well as the various regulatory proteins, that are involved in regulating the process of blood stem cell fate.
Their research has also yielded unexpected results: As many as 50% of these regulatory sequences are established and opened during intermediate stages of cell development. This means that epigenetics is active at stages in which it had been thought that cell destiny was already set. “This changes our whole understanding of the process of blood stem cell fate decisions,” says Lara-Astiaso, “suggesting that the process is more dynamic and flexible than previously thought.”
Although this research was conducted on mouse blood stem cells, the scientists believe that the mechanism may hold true for other types of cells. “This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” says Weiner.
Discovering the exact regulatory DNA sequence controlling stem cell fate, as well as understanding its mechanism, holds promise for the future development of diagnostic tools, personalized medicine, potential therapeutic and nutritional interventions, and perhaps even regenerative medicine, in which committed cells could be reprogrammed to their full stem cell potential.
Dr. Ido Amit’s research is supported by the M.D. Moross Institute for Cancer Research; the J&R Center for Scientific Research; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Abramson Family Center for Young Scientists; the Wolfson Family Charitable Trust; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Leona M. and Harry B. Helmsley Charitable Trust; Sam Revusky, Canada; the Florence Blau, Morris Blau and Rose Peterson Fund; the estate of Ernst and Anni Deutsch; the estate of Irwin Mandel; and the estate of David Levinson. Dr. Amit is the incumbent of the Alan and Laraine Fischer Career Development Chair.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to scientists, students, technicians, and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials, and developing new strategies for protecting the environment.
RESEARCHERS IDENTIFY A BRAIN “SWITCHBOARD” IMPORTANT IN ATTENTION AND SLEEP
From the FMS Global News Desk of Jeanne Hambleton Embargoed: 14-Aug-2014
Source : NYU Langone Medical Center Citations Cell
Newswise — New York City, August 14, 2014 – Researchers at NYU Langone Medical Center and elsewhere, using a mouse model, have recorded the activity of individual nerve cells in a small part of the brain that works as a “switchboard,” directing signals coming from the outside world or internal memories. Because human brain disorders such as schizophrenia, autism, and post-traumatic stress disorder typically show disturbances in that switchboard, the investigators say the work suggests new strategies in understanding and treating them.
In a study to be published in the journal Cell online Aug. 14, a team led by Michael Halassa, MD, PhD, assistant professor of psychiatry, neuroscience and physiology, and a member of the NYU Neuroscience Institute, showed how neurons in the thalamic reticular nucleus (TRN) — the so-called switchboard — direct sensory signals such as vision from the outside world, and internal information such as memories, to their appropriate destinations.
“We have never been able to observe as precisely how this structure worked before,” says Dr. Halassa. “This study shows us how information can be routed in the brain, giving us tremendous insight into how it might be broken in psychiatric disorders.”
For the study, researchers used a multi-electrode technique to record the activity of individual neurons in the TRN, a thin layer of nerve cells that covers the thalamus, a structure in the forebrain that relays information to the cerebral cortex, the seat of higher-level functions such as learning and language. TRN cells are known to send inhibitory signals to the thalamus, determining which information is blocked.
The activity of TRN cells, the researchers found, depended on whether the mouse was asleep or awake and alert. TRN cells that controlled sensory input were far more active during sleep, particularly during the periods of sleep when brief bursts of fast-cycling brain waves, called spindles, occur. Sleep spindles, which are associated with blocking sensory input during sleep, are known to be diminished among people with autism and schizophrenia.
Dr. Halassa says the new findings suggest that faulty TRN cells may be disrupting the appropriate filtering of information in these conditions. His group is now exploring this filtering process in animal models of schizophrenia and autism.
In experiments with alert mice, Dr. Halassa’s group found that sensory TRN cells fired very little. This suggested that while these neurons block the flow of external information during sleep, they facilitate the flow of information when an animal is awake and alert.
By contrast, TRN cells that control the flow of internal signals behaved in an opposite fashion, firing very little in sleep. This lowered level of activity, Dr. Halassa suspects, may allow memories to form, which is known to occur during sleep. The thalamus has nerve connections to the hippocampus, which plays an important role in learning and memory.
In a second part of the study, Dr. Halassa’s group employed a technique called optogenetics, which uses light to turn nerve cells on and off, to test whether altering TRN nerve cell firing affected attention behavior in the mice.
In one experiment, mice learned to associate a visual stimulus with food. Well-rested mice took just a second or two to find food when a stimulus was presented, while sleep-deprived mice took much longer. By turning on TRN cells that specifically controlled the visual part of the thalamus, as would happen normally in sleep, the rested mice behaved like they were sleep deprived. On the other hand, when the researchers turned off these TRN cells, sleep-deprived mice quickly found the food.
“With a flick of a light switch, we seemed able to alter the mental status of the mice, changing the speed at which information can travel in the brain,” says Dr. Halassa. Mapping brain circuits and disrupting their pathways will hopefully lead to new treatment targets for a range of neuropsychiatric disorders, he adds.
In addition to Halassa, other NYU Langone researchers involved in this study were Zhe Chen, PhD, and Ralf Wimmer, PhD. Additional research support was provided by Philip Brunetti and Matthew Wilson, PhD, at the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology in Cambridge, Mass.; Shengli Zhao, PhD, and Fan Wang, PhD, at Duke University in Durham, NC; Basilis Zukopoulos, PhD, at Boston University; and Emery Brown, MD, PhD, at Harvard University and the Massachusetts Institute of Technology.
About NYU Langone Medical Center:
NYU Langone Medical Center, a world-class, patient-centered, integrated academic medical center, is one of the nation’s premier centers for excellence in clinical care, biomedical research, and medical education. Located in the heart of Manhattan, NYU Langone is composed of four hospitals — Tisch Hospital, its flagship acute care facility; Rusk Rehabilitation; the Hospital for Joint Diseases, the Medical Center’s dedicated inpatient orthopaedic hospital; and Hassenfeld Children’s Hospital, a comprehensive pediatric hospital supporting a full array of children’s health services across the Medical Center — plus the NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The Medical Center’s tri-fold mission to serve, teach, and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education, and research.
COOL TEMPERATURE ALTERS HUMAN FAT AND METABOLISM
From the FMS Global News Desk of Jeanne Hambleton July 28, 2014 NIH Research Matters National Institute of Health
Men exposed to a cool environment overnight for a month had an increase in brown fat with corresponding changes in metabolism.
The finding hints at new ways to alter the body’s energy balance to treat conditions such as obesity and diabetes.
Humans have several types of fat. White fat stores extra energy. Too much white fat, a characteristic of obesity, increases the risk of type 2 diabetes and other diseases.
Brown fat, in contrast, burns chemical energy to create heat and help maintain body temperature. Researchers have previously shown that, in response to cold, white fat cells in both animals and humans take on characteristics of brown fat cells.
A team led by Dr. Francesco S. Celi of Virginia Commonwealth University and Dr. Paul Lee, now at the Garvan Institute of Medical Research in Australia, explored the effects of ambient temperature on brown fat and metabolism. The study was supported in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIH Clinical Center. Results appeared online on June 22, 2014, in Diabetes.
The researchers had 5 healthy men, average age 21 years, reside for 4 months in a clinical research unit in the NIH Clinical Center in Bethesda, Maryland. The men engaged in regular activities during the day and then returned to their private room each evening. The temperature of the room was set to 24 °C (75 °F) during the first month, 19 °C (66 °F) the second month, 24 °C again for the third month, and 27 °C (81 °F) the remaining month.
The participants were exposed to the temperature for at least 10 hours each night. They wore standard hospital clothing and had bed sheets only. All meals were provided, with calorie and nutrient content carefully controlled and all consumption monitored. At the end of each month, the men underwent extensive evaluations, including energy expenditure testing, muscle and fat biopsies, and PET/CT scanning of an area of the neck and upper back region to measure brown fat volume and activity.
After a month of exposure to mild cold, the participants had a 42% increase in brown fat volume and a 10% increase in fat metabolic activity. These alterations returned to near baseline during the following month of neutral temperature, and then were completely reversed during the final month of warm exposure. All the changes occurred independently of seasonal changes.
The increase in brown fat following a month of cold exposure was accompanied by improved insulin sensitivity after a meal during which volunteers were exposed to mild cold. Prolonged exposure to mild cold also resulted in significant changes in metabolic hormones such as leptin and adiponectin. There were no changes in body composition or calorie intake.
The findings suggest that humans may acclimate to cool temperature by increasing brown fat, which in turn may lead to improvements in glucose metabolism. These changes can be dampened or reversed following exposure to warmer temperatures.
“The big unknown until this study was whether or not we could actually manipulate brown fat to grow and shrink in a human being,” Lee says. “The improvement in insulin sensitivity accompanying brown fat gain may open new avenues in the treatment of impaired glucose metabolism.”
—by Carol Torgan, Ph.D.