Every cell contains a tiny clock called a telomere, which shortens each time the cell divides. Short telomeres are linked to a range of human diseases, including HIV, osteoporosis, heart disease and aging. Previous studies show that an enzyme within the cell, called telomerase, keeps immune cells young by preserving their telomere length and ability to continue dividing.

UCLA scientists found that the stress hormone cortisol suppresses immune cells’ ability to activate their telomerase. This may explain why the cells of persons under chronic stress have shorter telomeres.

The study reveals how stress makes people more susceptible to illness. The findings also suggest a potential drug target for preventing damage to the immune systems of persons who are under long-term stress, such as caregivers to chronically ill family members, as well as astronauts, soldiers, air traffic controllers and people who drive long daily commutes.

Rita Effros, professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA, and a member of the Jonsson Cancer Center, Molecular Biology Institute and UCLA AIDS Institute, is available for interviews.

“When the body is under stress, it boosts production of cortisol to support a “fight or flight” response,” explains Effros. “If the hormone remains elevated in the bloodstream for long periods of time, though, it wears down the immune system. We are testing therapeutic ways of enhancing telomerase levels to help the immune system ward off cortisol’s effect. If we’re successful, one day a pill may exist to strengthen the immune system’s ability to weather chronic emotional stress.”

The research was published in the May issue of the peer-reviewed journal Brain, Behavior and Immunity.

The study was supported by the National Institute of Aging, National Institute of Allergy and Infectious Disease, the Geron Corp. and TA Therapeutics, Ltd.

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Brain cells known as neurons process information by joining into complex networks, transmitting signals to each other across junctions called synapses. But “neurons don’t just connect to other neurons,” emphasizes Z. Josh Huang, Ph.D., “in a lot of cases, they connect to very specific partners, at particular spots.”

Dr. Huang, a professor at Cold Spring Harbor Laboratory (CSHL), leads a team that has identified molecules guiding this highly specific neuronal targeting in the developing brains of mice. The researchers report in PLoS Biology that in some cases, these molecular guides — non-signaling brain cells known as glia — form a kind of scaffold.  This scaffold, in turn, directs the growth of nerve fibers and their connections between specific types of neurons.

As they learn through research like this how the brain develops its complex wiring, the scientists hope they can clarify what goes wrong in disorders like autism.

The Cerebellum’s ‘Organized Architecture’

Distinctive wiring patterns are unmistakable in the cerebellum, a brain region best known for controlling movement, in both mice and people. Compared to regions involved in more sophisticated functions like vision and thought, “the cerebellum is an easier place to start, because of its very organized architecture,” Dr. Huang says, although he notes that other parts of the brain have their own specific wiring patterns.

Central to the wiring architecture of the cerebellum are so-called Purkinje cells, a type of neuron that deploys a bushy array of fibers called dendrites that extend through layers of cerebellar territory. The dendrites gather signals from many other neurons in the cerebellum and send signals to other parts of the body.

The complex wiring pattern emerges during the early growth of the brain, when individual neurons migrate from their places of origin in other brain regions and emit filaments called axons that connect to particular parts of other neurons, such as the dendrites. Dr. Huang likens this process to the address on a letter that brings it from another country directly to your door by specifying the country, state, city, street, and house number. He and other brain researchers have learned much about the higher levels of this addressing scheme, identifying, for instance, chemical signals that guide axons to the right section of the brain, and different signals that lead them to the appropriate layer within that section.

How Neurons Form Synapses

Only recently, however, have Dr. Huang and his colleagues traced the chemical signals leading neurons to form synapses with specific parts of other neurons. Such sub-cellular specificity is critical to ensure the precision and reliability of communication among neurons. Synapses are the tiny gaps across which nerve cells exchange signals, conveyed by chemicals called neurotransmitters.

A few years ago, Dr. Huang’s team established that a protein from the immunoglobulin family directs one group of cerebellar neurons to connect with a specific part of Purkinje cells. Immunoglobulin proteins are best known for acting as antibodies in the immune system, where they take on myriad forms to attack new invaders. Here, however, they are observed to be involved in the wiring of the brain.

“The striking feature is that there is a lot of capacity for variety” in immunoglobulin molecules, Dr. Huang explains. In the nervous system, their versatility may help them guide cells to form synapses with specific partners. Intriguingly, Dr. Huang adds, immunoglobulins have been implicated in neural developmental disorders, such as autism. “There is good evidence that these disorders involve miswiring of the nervous system,” Dr. Huang says, which may reflect a problem with immunoglobulin-guided synapse formation.

A Guiding Scaffold Made of Glial Cells

In the work reported in their newly published paper, Dr. Huang’s team traced the sub-cellular targeting of a different set of cerebellar neurons called stellate cells, which make numerous connections to the dendritic “bush” emanating from clumps of Purkinje cells. Unlike the cells they had studied previously, however, these neurons need help to form synapses. The researchers developed sophisticated techniques to label different cell types with chemical markers, and found that non-signaling cells called glia act as a scaffold, guiding the growing axons of the stellate cells and determining where they form synapses to the Purkinje cells.

In this role, the glia act something like “matchmakers” to bring the stellate and Purkinje cells together. But Dr. Huang notes that the scaffold of glia interspersed among the neurons allows each stellate cell to make contact to many different Purkinje cells. A direct attraction between stellate and Purkinje cells, he suggests, might lead two cells two pair up exclusively.

“Bergmann Glia and the Recognition Molecule CHL1 Organize GABAergic Axons and Direct Innervation of Purkinje Cell Dendrites” appears in the April, 2008 edition of the journal PLoS Biology. The complete citation is: Fabrice Ango, Caizhi Wu, Johannes J. Van der Want, Priscilla Wu, Melitta Schachner, Z. Josh Huang
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pbio.0060103#aff1.

The paper is available online at http://dx.doi.org/10.1371/journal.pbio.0060103.

Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.

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Although every cell of our bodies contains the same genetic instructions, specific genes typically act only in specific cells at particular times. Other genes are “silenced” in a variety of ways. One mode of gene silencing depends upon the way DNA, the genetic material, is packed in the nucleus of cells.

When packed very tightly around complexes of proteins called histones, the DNA double helix is rendered physically inaccessible to molecules that mediate gene expression. Now, a research team that includes Michael Q. Zhang, Ph.D., a professor at Cold Spring Harbor Laboratory (CSHL), has published a comprehensive analysis of modification patterns in histones.

Using a new technology called ChIP-Seq, the team identified 39 histone modifications, including a “core set” of 17 modifications that tended to occur together and were associated with genes observed to be active.

Modification Patterns With Different “Personalities”

Scientists have long known that chemical changes at particular locations in histone complexes influence how tightly the DNA is wrapped around the histones. “But it is important to know whether particular modifications occur together in characteristic patterns, or if these patterns can predict gene activities,” Dr. Zhang explained.

At the heart of the team’s efforts to determine this, Keji Zhao, Ph.D., of the National Heart, Blood, and Lung Institute of the National Institutes of Health, and his colleagues developed a method to map modifications in human white blood cells known as CD4+ T cells. First they used an enzyme to cut the DNA into short segments, which remained attached to histone “spools.” For each of 39 distinct histone modifications, the scientists used an antibody to extract matching histone-DNA combinations. Finally, they used the ChIP-Seq DNA-sequencing technology to determine which parts of the genome were bound to each type of modified histone.

The team’s most recent research, published in the July 2008 issue of Nature Genetics, maps the DNA locations that bind to histones containing molecular configurations called acetyl groups at 18 different positions in the “tails” of the histone proteins. The scientists combined this information with earlier maps for 19 different changes called methylation modifications, and for replacement of one of the histone proteins with a well-known variant.

The various modifications showed distinctive “personalities,” each preferentially associating with particular regulatory regions of genes.

Looking for Patterns

Mapping many modifications enabled the researchers to explore whether different types tend to appear together in the same type of DNA regulatory regions. They found that some recurring combinations did occur frequently at “promoter” and “enhancer” regions in DNA, which are known to increase the activity of nearby genes. In particular, the team identified one combination of 17 modifications that was present in more than a quarter of the more than 12,000 promoter regions they examined.

On average, the genes corresponding to this “backbone” set were expressed more actively. That is to say, they were activated, setting the cellular machinery in motion to produce specific proteins, the workhorses of most life processes.

The rich relationships detected by the researchers among the various histone modifications suggests that specific combinations might carry specific meanings. Previous researchers have proposed a “histone code” hypothesis, which posits that a particular combination of modifications may be recognized by a particular protein module. Some scientists believe such histone code may determine the activity of a given gene.

But, cautions Dr. Zhang, while there are patterns, like the backbone, that are highly correlated, “none of them has exact predictive value.” He maintains “there must be something else” that also affects gene activity.

Since genes with higher or lower expression levels may have the same patterns of modification, and not all active genes share a common pattern, the reality is likely more complex than a universal histone code that predicts exact gene expression level. Nonetheless, the new research provides a rich data source for understanding how specific combinations of histone modifications modulate the effects of many genes, in turn helping to modify activity within and among cells. “Critical future research should focus on finding proteins that target histone modifications to genetic regions with particular sequences,” Dr. Zhang emphasized.

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