Monthly Archives: October 2009

FLASH dances with death and mRNA

Whether it was Daniel DeFoe or Benjamin Franklin, whoever coined the phrase, “Nothing is certain but death and taxes,” clearly hadn’t a clue of another of life’s immutable pairings:  histone proteins and DNA.

Histones are the chief protein components of chromatin — the protein/DNA combo of which chromosomes are made — and they act as a scaffold to allow the packaging of DNA into a condensed form that fits inside the nucleus of a cell. As the DNA interacts with histones and with metabolic signals from within the cell, these proteins help regulate gene expression.

But how does the histone component of this dynamic duo get started in the first place?  The answer, according to new research from UNC,  appears in [a] FLASH.

This protein is already shown to play a role in initiating apoptosis, or the normal process of programmed cell death, and is now the latest key player in the molecular dance essential for DNA replication within cells.

According to senior study author Zbigniew Dominski, Ph.D., associate professor of biochemistry and biophysics, the new study demonstrates that FLASH is  required for the proper synthesis of histone messenger RNA, which gives rise to histone proteins.

“FLASH is crucial for the production of histone messenger RNA, without which the cell can’t make the histone proteins around which DNA is packaged,” says Dominski. “Our study suggests for the first time that a potential link exists between the processes of histone messenger RNA formation and apoptosis.”

The research is described in the October 23rd issue of the journal Molecular Cell.

For the study, Dominski adapted a laboratory system that reproduces in the test tube what normally occurs in the cell when FLASH participates in the biochemical cleavage event that results in mature histone messenger RNA. This enabled his team to explore what might occur when FLASH was added or removed.

“We could then figure out exactly what portion of FLASH would restore the protein’s function in generating histone mRNAs and remarkably, only the first 100 or so amino acids are required.  The remaining 2,000 amino acids of this large protein likely control other processes in the cell, including apoptosis and DNA replication” he explained.

Co-author William F. Marzluff, Ph.D., is Distinguished Professor of biochemistry & biophysics. He notes that FLASH is the first component found in this protein complex that integrates or initiates many cellular functions — DNA replication, apoptosis, histone production.  “Having this small piece of the puzzle makes it a lot easier to identify others.”

Except for a certain somebody who originally paired the certainty of death and taxes.

Les Lang

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From gene deletion to schizophrenia?

Scientists have long thought the faulty neural wiring that predisposes individuals to behavioral disorders like autism and psychiatric diseases like schizophrenia must occur during development. But no one has ever shown that a risk gene for the disease actually disrupts brain development.

Now, UNC scientists  have found that the 22q11 gene deletion on chromosome 22 – a mutation that confers the highest known genetic risk for schizophrenia – is associated with changes in the development of the brain that ultimately affect how its circuit elements are assembled.

In a genetic animal model, the researchers discovered that the gene deletion alters the number of a critical subset of neurons that end up in the brain’s cerebral cortex – the region critical to reasoning and memory. The defect also causes another type of nerve cell – called GABAergic neurons – to be misplaced within the brain’s cortical layers, resulting in a subtle miswiring of the organ.

“For practically ever other disease, we know what cells take a hit,” said senior study author Anthony LaMantia, Ph.D., professor of cell and molecular physiology and co-director of the Silvio M. Conte Center for Research in Mental Disorders at the UNC School of Medicine.

“For multiple sclerosis the myelinating oligodendrocytes in the brain falter, for Lou Gehrig’s disease the motor neurons in the brain stem degenerate. But we really had no idea what was happening in schizophrenia, or in any of the psychiatric diseases for that matter – until now.”

The study was presented October 17, 2009  at the Society for Neuroscience meeting in Chicago, by Daniel Meechan, Ph.D., post-doctoral fellow in the LaMantia laboratory and the first author of the recent paper in Proceedings of the National Academy of Sciences that details the findings.

Les Lang

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GO accelerator for genome research

Ever since the first genome sequence was published in 2001, scientists have been working to figure out what the sequence means.  An analogy is walking across a desert and finding a large book in a language you don’t know, then trying to figure out what the book is saying.

“In the case of the human genome, the book is a blueprint to building cells—and ultimately—the whole human.  But we don’t yet understand its language,” said Morgan Giddings, Ph.D., associate professor of microbiology and immunology and of biomedical engineering at the University of North Carolina at Chapel Hill.

Morgan Giddings, Ph.D., left, and Xian Chen, Ph.D., right. Photo by Courtney Potter

Morgan Giddings, Ph.D., left, and Xian Chen, Ph.D., right. Photo by Courtney Potter

Giddings and UNC colleague Xian Chen, Ph.D., associate professor of biochemistry and biophysics, have been developing methods for decoding the human blueprint by studying the things the blueprint produces: proteins.  They relate the proteins back to the blueprint itself, to further decode the language of the genome blueprint.

Giddings and Chen have been awarded a $1.6 million 2-year “Grand Opportunities” (GO) grant from the National Human Genome Research Institute to accelerate this research.  Their effort will be part of a consortium of investigators studying the human genome blueprint, titled the “ENCyclopedia Of DNA Elements” (ENCODE).  The consortium’s overall goal is to assemble a comprehensive catalog of functional elements in the human genome.

With their GO grant, Giddings and Chen will generate, analyze, and release to the public large-scale data sets that allow linking of the protein products in cells to their genomic blueprints.  According to Giddings, “this will significantly promote our understanding of the language of the human genome, enhancing efforts to solve pressing human health issues like heart disease and cancer by understanding how errors in the blueprint lead to disease, and how we might fix those errors.”

Giddings is a member of the Carolina Center for Genome Sciences, and Chen is technology development director for the UNC Proteomics Core.

As to impact  on the local North Carolina economy, the new grant is expected to  bring 4-6 new high-tech jobs to the Triangle.

NHGRI has awarded approximately $22 million of American Recovery and Reinvestment Act 2009 funds to support research aimed at identifying and understanding the genome’s functional elements.

Les Lang

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Neural lesson in migration

In laying down the neural circuitry of the developing brain, billions of neurons must first migrate to their correct destinations and then form complex synaptic connections with their new neighbors.

When the process goes awry, neurodevelopmental disorders such as mental retardation, dyslexia or autism may result.

Scientists led by Franck Polleux, Ph.D., associate professor of pharmacology at the University of North Carolina at Chapel Hill School of Medicine have now discovered that establishing the neural wiring necessary to function normally depends on the ability of neurons to make finger-like projections of their membrane called filopodia.

The finding, published as the cover story of the Sept. 4 issue of the journal Cell, indicates that the current notion regarding how cells change shape, migrate or differentiate needs to be revisited.

According to Polleaux, scientists have thought that the only way for a cell to morph and move is through the action of the cytoskeleton or the scaffold inside the cell, pushing membrane forward or sucking it in.

But Polleux’s study shows that the brain protein srGAP2 can also impose cell shape by directly bending membranes, forming filopodia as a mean to control the migration and branching of neurons during brain development.

Les Lang   (Video produced by Chris Carmichael)

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Discovery, discovery, discovery

“Location. Location. Location,” is a mantra in real estate circles, but when it comes to molecular science nowadays, the phrase appears to be “Discovery. Discovery. Discovery.”

This takes on particular importance when the view from the lab bench after the last puff of smoke clears reveals what could be potential applications for human health and disease, especially for future interventions in cancer.

A good example are the recent findings from the lab of  Victoria Bautch, Ph.D., professor of biology at the University of North Carolina at Chapel Hill.

In a paper published recently in the journal Developmental Cell (the cover story for that issue), Bautch and co-authors reported having identified a new biological process that spurs the growth of new blood vessels.

Up until now, scientists thought that the molecular signals to form new blood vessel sprouts came from outside the vessel. But new research from UNC has shown that signals can also come from within the blood vessel, pushing new blood vessel sprouts outward.

In experiments using mouse embryonic stem cells and mouse retinas, the researchers found that defects in a protein called Flt-1 lead to abnormal sprouts and poor vessel networks. Other research recently showed that levels of Flt-1 protein are particularly low in the dilated and leaky blood vessels that supply tumors with oxygen.

“The blood vessels themselves seem to participate in the process guiding the formation of the vascular network,” said  Bautch. “They do not just passively sit there getting acted upon by signals coming from the outside in. Rather, they produce internal cues that interact with external cues to grow.”

The findings could give important insights into the formation of the vasculature needed to feed new tumors.

Bautch, who is also a member of the Program in Molecular Biology and Biotechnology, the UNC McAllister Heart Institute and UNC Lineberger Comprehensive Cancer Center, notes that the more scientists understand about the sophistication and complexity of the mechanisms guiding the formation of blood vessel sprouts, the better equipped they will be to develop therapeutic interventions to produce or to halt new blood vessels.

Les Lang. (Video produced by Courtney Potter)

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