Brain Development Is Guided by Junk DNA That Isn't Really Junk

Brain Development Is Guided by Junk DNA That Isn't Really Junk

  8:02:00 AM    Science Lover

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Specific DNA once dismissed as junk plays an important role in brain development and might be involved in several devastating neurological diseases, UC San Francisco scientists have found.

UCSF researchers have uncovered a role in brain development and in neurological disease for little appreciated molecules called long noncoding RNA. In this image, fluorescent dyes track the presence of the RNA molecules and the genes they affect in the developing mouse brain. (Credit: Image courtesy of Alexander Ramos)

Their discovery in mice is likely to further fuel a recent scramble by researchers to identify roles for long-neglected bits of DNA within the genomes of mice and humans alike.

While researchers have been busy exploring the roles of proteins encoded by the genes identified in various genome projects, most DNA is not in genes. This so-called junk DNA has largely been pushed aside and neglected in the wake of genomic gene discoveries, the UCSF scientists said.

In their own research, the UCSF team studies molecules called long noncoding RNA (lncRNA, often pronounced as "link" RNA), which are made from DNA templates in the same way as RNA from genes.

"The function of these mysterious RNA molecules in the brain is only beginning to be discovered," said Daniel Lim, assistant professor of neurological surgery, a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, and the senior author of the study, published online April 11 in the journal Cell Stem Cell.

Alexander Ramos, a student enrolled in the MD/PhD program at UCSF and first author of the study, conducted extensive computational analysis to establish guilt by association, linking lncRNAs within cells to the activation of genes.

Ramos looked specifically at patterns associated with particular developmental pathways or with the progression of certain diseases. He found an association between a set of 88 long noncoding RNAs and Huntington's disease, a deadly neurodegenerative disorder. He also found weaker associations between specific groups of long noncoding RNAs and Alzheimer's disease, convulsive seizures, major depressive disorder and various cancers.

"Alex was the team member who developed this new research direction, did most of the experiments, and connected results to the lab's ongoing work," Lim said. The study was mostly funded through Lim's grant - a National Institutes of Health (NIH) Director's New Innovator Award, a competitive award for innovative projects that have the potential for unusually high impact.

Unlike messenger RNA, which is transcribed from the DNA in genes and guides the production of proteins, lncRNA molecules do not carry the blueprints for proteins. Because of this fact, they were long thought to not influence a cell's fate or actions.

Nonetheless, lncRNAs also are transcribed from DNA in the same way as messenger RNA, and they, too, consist of unique sequences of nucleic acid building blocks.

Evidence indicates that lncRNAs can tether structural proteins to the DNA-containing chromosomes, and in so doing indirectly affect gene activation and cellular physiology without altering the genetic code. In other words, within the cell, lncRNA molecules act "epigenetically" -- beyond genes -- not through changes in DNA.

The brain cells that the scientists focused on the most give rise to various cell types of the central nervous system. They are found in a region of the brain called the subventricular zone, which directly overlies the striatum. This is the part of the brain where neurons are destroyed in Huntington's disease, a condition triggered by a single genetic defect.

Ramos combined several advanced techniques for sequencing and analyzing DNA and RNA to identify where certain chemical changes happen to the chromosomes, and to identify lncRNAs on specific cell types found within the central nervous system. The research revealed roughly 2,000 such molecules that had not previously been described, out of about 9,000 thought to exist in mammals ranging from mice to humans.

In fact, the researchers generated far too much data to explore on their own. The UCSF scientists created a website through which their data can be used by others who want to study the role of lncRNAs in development and disease.

"There's enough here for several labs to work on," said Ramos, who has training grants from the California Institute for Regenerative Medicine (CIRM) and the NIH.

"It should be of interest to scientists who study long noncoding RNA, the generation of new nerve cells in the adult brain, neural stem cells and brain development, and embryonic stem cells," he said.

Other co-authors who worked on the study include UCSF postdoctoral fellows Aaron Diaz, PhD, Abhinav Nellore, PhD, Michael Oldham, PhD, Jun Song, PhD, Ki-Youb Park, PhD, and Gabriel Gonzales-Roybal, PhD; and MD/PhD student Ryan Delgado. Additional funders of the study included the Sontag Foundation and the Sandler Foundation.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. 
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Chinese Medicine Yields Secrets: Atomic Mechanism of Two-Headed Molecule Derived from Chang Shan, a Traditional Chinese Herb

Chinese Medicine Yields Secrets: Atomic Mechanism of Two-Headed Molecule Derived from Chang Shan, a Traditional Chinese Herb

  9:49:00 AM    Science Lover

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The mysterious inner workings of Chang Shan -- a Chinese herbal medicine used for thousands of years to treat fevers associated with malaria -- have been uncovered thanks to a high-resolution structure solved at The Scripps Research Institute (TSRI).

Scripps Research Institute scientists have determined a molecular 
 structure that helps explain how the Chinese herbal medicine 
Chang Shan works. (Credit: Image courtesy of the Schimmel lab.)

Described in the journal Nature this week, the structure shows in atomic detail how a two-headed compound derived from the active ingredient in Chang Shan works. Scientists have known that this compound, called halofuginone (a derivative of the febrifugine), can suppress parts of the immune system -- but nobody knew exactly how.

The new structure shows that, like a wrench in the works, halofuginone jams the gears of a molecular machine that carries out "aminoacylation," a crucial biological process that allows organisms to synthesize the proteins they need to live. Chang Shan, also known as Dichroa febrifuga Lour, probably helps with malarial fevers because traces of a halofuginone-like chemical in the herb interfere with this same process in malaria parasites, killing them in an infected person's bloodstream.

"Our new results solved a mystery that has puzzled people about the mechanism of action of a medicine that has been used to treat fever from a malaria infection going back probably 2,000 years or more," said Paul Schimmel, PhD, the Ernest and Jean Hahn Professor and Chair of Molecular Biology and Chemistry and member of The Skaggs Institute for Chemical Biology at TSRI. Schimmel led the research with TSRI postdoctoral fellow Huihao Zhou, PhD.

Halofuginone has been in clinical trials for cancer, but the high-resolution picture of the molecule suggests it has a modularity that would make it useful as a template to create new drugs for numerous other diseases.

The Process of Aminoacylation and its Importance to Life

Aminoacylation is a crucial step in the synthesis of proteins, the end products of gene expression. When genes are expressed, their DNA sequence is first read and transcribed into RNA, a similar molecule. The RNA is then translated into proteins, which are chemically very different from DNA and RNA but are composed of chains of amino acid molecules strung together in the order called for in the DNA.

Necessary for this translation process are a set of molecules known as transfer RNAs (tRNAs), which shuttle amino acids to the growing protein chain where they are added like pearls on a string. But before the tRNAs can move the pearls in place, they must first grab hold of them.

Aminoacylation is the biological process whereby the amino acid's pearls are attached to these tRNA shuttles. A class of enzymes known as aminoacyl-tRNA synthetases is responsible for attaching the amino acids to the tRNAs, and Schimmel and his colleagues have been examining the molecular details of this process for years. Their work has given scientists insight into everything from early evolution to possible targets for future drug development.

Over time what has emerged as the picture of this process basically involves three molecular players: a tRNA, an amino acid and the aminoacyl-tRNA synthetase enzyme that brings them together. A fourth molecule called ATP is a microscopic form of fuel that gets consumed in the process.

The new work shows that halofuginone gets its potency by interfering with the tRNA synthetase enzyme that attaches the amino acid proline to the appropriate tRNA. It does this by blocking the active site of the enzyme where both the tRNA and the amino acid come together, with each half of the halofuginone blocking one side or the other.

Interestingly, said Schimmel, ATP is also needed for the halofuginone to bind. Nothing like that has ever been seen in biochemistry before.

"This is a remarkable example where a substrate of an enzyme (ATP) captures an inhibitor of the same enzyme, so that you have an enzyme-substrate-inhibitor complex," said Schimmel.

The article, "ATP-Directed Capture of Bioactive Herbal-Based Medicine on Human tRNA Synthetase," by Huihao Zhou, Litao Sun, Xiang-Lei Yang and Paul Schimmel was published in the journal Nature on Dec. 23, 2012.

This work was supported by the National Institutes of Health through grants #GM15539, #23562 and #88278 and by a fellowship from the National Foundation for Cancer Research.

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Entire Genetic Sequence of Individual Human Sperm Determined

Entire Genetic Sequence of Individual Human Sperm Determined

  11:46:00 AM    Science Lover

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The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete -- the only cells that become a child and through which parents pass on physical traits.

Every sperm cell looks essentially the same, with that characteristic tadpole appearance. But inside, sperm cells carry differences within their genes -- even cells from the same man. Now, researchers provide a detailed picture of how the cell's DNA varies in a new study published in the July 20, 2012 issue of the Cell Press journal Cell. The techniques used could be helpful for understanding male reproductive disorders or, when applied to other areas of research, for characterizing normal and diseased cells in the body. (Credit: iStockphoto/Alexandr Mitiuc)

"This represents the culmination of nearly a decade of work in my lab," said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics. "We now have devices that will allow us to routinely amplify and sequence to a high degree of accuracy the entire genomes of single cells, which has far-ranging implications for the study of cancer, infertility and many other disorders."

Quake is the senior author of the research, published July 20 in Cell. Graduate student Jianbin Wang and former graduate student H. Christina Fan, PhD, now a senior scientist at ImmuMetrix, share first authorship of the paper.

Sequencing sperm cells is particularly interesting because of a natural process called recombination that ensures that a baby is a blend of DNA from all four of his or her grandparents. Until now, scientists had to rely on genetic studies of populations to estimate how frequently recombination had occurred in individual sperm and egg cells, and how much genetic mixing that entailed.

"Single-sperm sequencing will allow us to chart and understand how recombination differs between individuals at the finest scales. This is an important proof of principle that will allow us to study both fundamental dynamics of recombination in humans and whether it is involved in issues relating to male infertility," said Gilean McVean, PhD, professor of statistical genetics at the Wellcome Trust Centre for Human Genetics. McVean was not involved in the research.

The Stanford study showed that the previous, population-based estimates were, for the most part, surprisingly accurate: on average, the sperm in the sample had each undergone about 23 recombinations, or mixing events. However, individual sperm varied greatly in the degree of genetic mixing and in the number and severity of spontaneously arising genetic mutations. Two sperm were missing entire chromosomes. The study has long-ranging implication for infertility doctors and researchers.

"For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person," said study co-author Barry Behr, PhD, HCLD, professor of obstetrics and gynecology and director of Stanford's in vitro fertilization laboratory. "Now we can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems."

Most cells in the human body have two copies of each of 23 chromosomes, and are known as "diploid" cells. Recombination occurs during a process called meiosis, which partitions a single copy of each chromosome into a sperm (in a man) or egg (in a woman) cell. When a sperm and an egg join, the resulting fertilized egg again has a full complement of DNA.

To ensure an orderly distribution during recombination, pairs of chromosomes are lined up in tight formation along the midsection of the cell. During this snug embrace, portions of matching chromosomes are sometimes randomly swapped. The process generates much more genetic variation in a potential offspring than would be possible if only intact chromosomes were segregated into the reproductive cells.

"The exact sites, frequency and degree of this genetic mixing process is unique for each sperm and egg cell," said Quake, "and we've never before been able to see it with this level of detail. It's very interesting that what happens in one person's body mirrors the population average."

Major problems with the recombination process can generate sperm missing portions or even whole chromosomes, making them incapable of or unlikely to fertilize an egg. But it can be difficult for fertility researchers to identify potential problems.

"Most of the techniques we currently use to assess sperm viability are fairly crude," said Quake.

To conduct the research, Wang, Quake and Behr first isolated and sequenced nearly 100 sperm cells from the study subject, a 40-year-old man. The man has healthy offspring, and the semen sample appeared normal. His whole-genome sequence (obtained from diploid cells) has been previously sequenced to a high level of accuracy.

They then compared the sequence of the sperm with that of the study subject's diploid genome. They could see, by comparing the sequences of the chromosomes in the diploid cells with those in the haploid sperm cells, where each recombination event took place. The researchers also identified 25 to 36 new single nucleotide mutations in each sperm cell that were not present in the subject's diploid genome. Such random mutations are another way to generate genetic variation, but if they occur at particular points in the genome they can have deleterious effects.

It's important to note that individual sperm cells are destroyed by the sequencing process, meaning that they couldn't go on to be used for fertilization. However, the single-cell sequencing described in the paper could potentially be used to diagnose male reproductive disorders and help infertile couples assess their options. It could also be used to learn more about how male fertility and sperm quality change with increasing age.

"This could serve as a new kind of early detection system for men who may have reproductive problems," said Behr, who also co-directs Stanford's reproductive endocrinology and infertility program. "It's also possible that we could one day use other, correlating features to harmlessly identify healthy sperm for use in IVF. In the end, the DNA is the raw material that ultimately defines a sperm's potential. If we can learn more about this process, we can better understand human fertility."

The research was supported by the National Institute of Health, the Chinese Scholarship Council and the Siebel Foundation.

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Researchers Watch Tiny Living Machines Self-Assemble

Researchers Watch Tiny Living Machines Self-Assemble

  1:05:00 PM    Science Lover

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Enabling bioengineers to design new molecular machines for nanotechnology applications is one of the possible outcomes of a study by University of Montreal researchers that was published in Nature Structural and Molecular Biology June 10. The scientists have developed a new approach to visualize how proteins assemble, which may also significantly aid our understanding of diseases such as Alzheimer's and Parkinson's, which are caused by errors in assembly.

Vallée-Bélisle and Michnick have developed a new 
approach to visualize how proteins assemble, which may 
also significantly aid our understanding of diseases such 
as Alzheimer’s and Parkinson’s, which are caused by errors 
in assembly. Here shown are two different assembly stages 
(purple and red) of the protein ubiquitin and the fluorescent 
probe used to visualize these stage (tryptophan: see yellow).

"In order to survive, all creatures, from bacteria to humans, monitor and transform their environments using small protein nanomachines made of thousands of atoms," explained the senior author of the study, Prof. Stephen Michnick of the university's department of biochemistry. "For example, in our sinuses, there are complex receptor proteins that are activated in the presence of different odor molecules. Some of those scents warn us of danger; others tell us that food is nearby." Proteins are made of long linear chains of amino acids, which have evolved over millions of years to self-assemble extremely rapidly -- often within thousandths of a split second -- into a working nanomachine. "One of the main challenges for biochemists is to understand how these linear chains assemble into their correct structure given an astronomically large number of other possible forms," Michnick said.

"To understand how a protein goes from a linear chain to a unique assembled structure, we need to capture snapshots of its shape at each stage of assembly said Dr. Alexis Vallée-Bélisle, first author of the study. "The problem is that each step exists for a fleetingly short time and no available technique enables us to obtain precise structural information on these states within such a small time frame. We developed a strategy to monitor protein assembly by integrating fluorescent probes throughout the linear protein chain so that we could detect the structure of each stage of protein assembly, step by step to its final structure."

The protein assembly process is not the end of its journey, as a protein can change, through chemical modifications or with age, to take on different forms and functions. "Understanding how a protein goes from being one thing to becoming another is the first step towards understanding and designing protein nanomachines for biotechnologies such as medical and environmental diagnostic sensors, drug synthesis of delivery," Vallée-Bélisle said.

This research was supported by the Natural Sciences and Engineering Research Council of Canada and Le fond de recherché du Québec, Nature et Technologie. The article, "Visualizing transient protein folding intermediates by tryptophan scanning mutagenesis," published in Nature Structural & Molecular Biology, was coauthored by Alexis Vallée-Bélisle and Stephen W. Michnick of the Département de Biochimie de l'Université de Montréal. The University of Montreal is known officially as Université de Montréal.

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Building Molecular 'Cages' to Fight Disease

Building Molecular 'Cages' to Fight Disease

  8:30:00 PM    Science Lover

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UCLA biochemists have designed specialized proteins that assemble themselves to form tiny molecular cages hundreds of times smaller than a single cell. The creation of these miniature structures may be the first step toward developing new methods of drug delivery or even designing artificial vaccines.

This is a molecular cage created by designing 
specialized protein puzzle pieces. Every color 
represents a separate protein, where cylindrical 
segments indicate rigid parts and ribbon-like 
segments indicate flexible parts of each protein 
chain. The grey sphere in the protein cage was 
placed there to indicate the empty space in the 
middle of the container and is not part of the 
molecular structure. (Credit: Todd Yeates, Yen-
Ting Lai/UCLA Chemistry and Biochemistry)

"This is the first decisive demonstration of an approach that can be used to combine protein molecules together to create a whole array of nanoscale materials," said Todd Yeates, a UCLA professor of chemistry and biochemistry and a member of the UCLA-DOE Institute of Genomics and Proteomics and the California NanoSystems Institute at UCLA.

Published June 1 in the journal Science, the research could be utilized to create cages from any number of different proteins, with potential applications across the fields of medicine and molecular biology.

UCLA graduate student Yen-Ting Lai, lead author of the study, used computer models to identify two proteins that could be combined to form perfectly shaped three-dimensional puzzle pieces. Twelve of these specialized pieces fit together to create a molecular cage a mere fraction of the size of a virus.

"If you just connect two random proteins together, you expect to get an irregular network," said Yeates, senior author of the study. "In order to control the geometry, the idea was to make a rigid link holding the two proteins in place as if they were parts of a toy puzzle."

The specifically designed proteins intermesh to form a hollow lattice that could act as a vessel for drug delivery, he said.

"In principle, it would be possible to attach a recognition sequence for cancer cells on the outside of the cage, with a toxin or some other 'magic bullet' contained inside," said Yeates. "That way, the drug could be delivered directly to certain targets like tumor cells."

At this stage, the assembled protein cages are porous enough that a drug placed inside would likely leak out during the delivery process, Lai said. His next project will involve constructing a new molecular cage with an interior that will be better sealed.

Another use for the versatile protein structures might be as artificial vaccines. Some traditional vaccines use an inactive surface protein from a virus to trick the body's immune system into thinking it is under attack. This method isn't always effective, because sometimes the protein in question doesn't look enough like the virus to trigger a strong response from the body's defenders.

However, by decorating the surface of a molecular cage with segments of virus-derived proteins, the tiny structures might better mimic a virus, stimulating an immune response even stronger than a traditional vaccine and better protecting the human recipient from illness.

Before these protein structures can be used in medical applications, the molecular containers themselves must be constructed from human-like proteins, rather than the currently employed bacterial proteins that the human body might immediately clear from circulation, Yeates said.

"Our first challenge will be repeating these kinds of designs with molecules that are less likely to generate a host immune response," he said. "Generally, we want to use proteins that look like human proteins so the body does not recognize them as foreign."

The idea of building complex, self-assembled protein structures has been Yeates' ambition since he published a paper outlining preliminary work on this method in 2001. Yet the concept remained on the back burner for 10 years until Yen-Ting Lai joined Yeates' research group. With three master's degrees -- in structural biology, bioinformatics and biomedical engineering -- Lai had the right combination of skills to bring the research to fruition, Yeates said.

This project is federally funded by the National Science Foundation. Other co-authors include UCLA senior staff scientist Duilio Cascio.

A second breakthrough

A second paper co-authored by Yeates creates similarly designed molecular cages using multiple copies of the same protein as building blocks. The scientists control the shape of the cage by computing the sequence of amino acids necessary to link the proteins together at the correct angles. The research, also published May 31 in Science, resulted from a collaboration between the UCLA team and professor David Baker at the University of Washington.

This alternative method represents a more versatile approach because it requires only one type of protein to form a structure, Yeates said. However, devising different kinds of links between the identical proteins remains a major challenge. Lead author Neil King, a postdoctoral scholar at the University of Washington and a former student of Yeates, took the numerous computer-generated possibilities and tested each version experimentally until he found one which produced the right behavior.

This research is federally funded by the National Institutes of Health and the U.S. Department of Energy. Other UCLA co-authors include senior staff researcher Michael Sawaya.

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Editing the Genome: Scientists Unveil New Tools for Rewriting the Code of Life

Editing the Genome: Scientists Unveil New Tools for Rewriting the Code of Life

  2:50:00 AM    Science Lover

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The power to edit genes is as revolutionary, immediately useful and unlimited in its potential as was Johannes Gutenberg's printing press. And like Gutenberg's invention, most DNA editing tools are slow, expensive, and hard to use -- a brilliant technology in its infancy. Now, Harvard researchers developing genome-scale editing tools as fast and easy as word processing have rewritten the genome of living cells using the genetic equivalent of search and replace -- and combined those rewrites in novel cell strains, strikingly different from their forebears.

Researchers have unveiled genome-engineering technologies capable of fundamentally re-engineering genomes from the nucleotide to the megabase scale. Treating the chromosome as both an editable and an evolvable template, the researchers have demonstrated methods to rewrite a cell's genome through powerful new tools for biotechnology, energy and agriculture. (Credit: iStockphoto/Zmeel Photography)

"The payoff doesn't really come from making a copy of something that already exists," said George Church, a professor of genetics at Harvard Medical School who led the research effort in collaboration with Joe Jacobson, an associate professor at the Media Lab at the Massachusetts Institute of Technology. "You have to change it -- functionally and radically."

Such change, Church said, serves three goals. The first is to add functionality to a cell by encoding for useful new amino acids. The second is to introduce safeguards that prevent cross-contamination between modified organisms and the wild. A third, related aim, is to establish multi-viral resistance by rewriting code hijacked by viruses. In industries that cultivate bacteria, including pharmaceuticals and energy, such viruses affect up to 20 percent of cultures. A notable example afflicted the biotech company Genzyme, where estimates of losses due to viral contamination range from a few hundred million dollars to more than $1 billion.

In a paper scheduled for publication July 15 in Science, the researchers describe how they replaced instances of a codon -- a DNA "word" of three nucleotide letters -- in 32 strains of E. coli, and then coaxed those partially-edited strains along an evolutionary path toward a single cell line in which all 314 instances of the codon had been replaced. That many edits surpasses current methods by two orders of magnitude, said Harris Wang, a research fellow in Church's lab at the Wyss Institute for Biologically Inspired Engineering who shares lead-author credit on the paper with Farren Isaacs, an assistant professor of molecular, cellular and developmental biology at Yale University and former Harvard research fellow, and Peter Carr, a research scientist at the MIT Media Lab.



In the genetic code, most codons specify an amino acid, a protein building block. But a few codons tell the cell when to stop adding amino acids to a protein chain, and it was one of these "stop" codons that the Harvard researchers targeted. With just 314 occurrences, the TAG stop codon is the rarest word in the E. coli genome, making it a prime target for replacement. Using a platform called multiplex automated genome engineering, or MAGE, the team replaced instances of the TAG codon with another stop codon, TAA, in living E. coli cells. (Unveiled by the team in 2009, the MAGE process has been called an evolution machine for its ability to accelerate targeted genetic change in living cells.)

While MAGE, a small-scale engineering process, yielded cells in which TAA codons replaced some but not all TAG codons, the team constructed 32 strains that, taken together, included every possible TAA replacement. Then, using bacteria's innate ability to trade genes through a process called conjugation, the researchers induced the cells to transfer genes containing TAA codons at increasingly larger scales. The new method, called conjugative assembly genome engineering, or CAGE, resembles a playoff bracket -- a hierarchy that winnows 16 pairs to eight to four to two to one -- with each round's winner possessing more TAA codons and fewer TAG, explains Isaacs, who invokes "March Madness."

"We're testing decades-old theories on the conservation of the genetic code," Isaacs said. "And we're showing on a genome-wide scale that we're able to make these changes."

Eager to share their enabling technology, the team published their results as CAGE reached the semifinal round. Results suggested that the final four strains were healthy, even as the team assembled four groups of 80 engineered alterations into stretches of the chromosome surpassing 1 million DNA base pairs. "We encountered a great deal of skepticism early on that we could make so many changes and preserve the health of these cells," Carr said. "But that's what we've seen."

The researchers are confident that they will create a single strain in which TAG codons are completely eliminated. The next step, they say, is to delete the cell's machinery that reads the TAG gene -- freeing up the codon for a completely new purpose, such as encoding a novel amino acid.

"We're trying to challenge people," Wang said, "to think about the genome as something that's highly malleable, highly editable."

This research was funded by U.S. Department of Energy and the National Science Foundation.

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