UCLA scientists identify 2,000 important genes.

Zebra finches

Can the song of a small bird provide valuable insights into human stuttering and speech-related disorders and conditions, including autism and stroke? New research by UCLA life scientists and colleagues provides reason for optimism.

The scientists discovered that some 2,000 genes in a region of the male zebra finch’s brain known as “Area X” are significantly linked to singing. More than 1,500 genes in this region, a critical part of the bird’s song circuitry, are being reported for the first time. Previously, a group of scientists including the UCLA team had identified some 400 genes in Area X. All the genes’ levels of expression change when the bird sings.

We did not know before that all of these genes are regulated by singing,” said Stephanie White, a UCLA associate professor of integrative biology and physiology and senior author of the new study. She believes the 2,000 genes — which are also shared by humans — are likely important for human speech.

The research is published in the online edition of the journal Neuron, a leading neuroscience journal, and will appear in an upcoming print edition.

“A method that (UCLA co-author) Steve Horvath developed lets us see what genes are changing together and, therefore, which genes are linked in a network,” White said. “We can see which are the hub genes that are the most connected to other genes, as in a social network — the popular kids. We can also identify the genetic equivalent of the lonely kids. Steve’s analysis lets us group the genes together and see who is interacting with whom.”

Many more genes are involved in vocalization than scientists had previously known. While language is uniquely human, it has components — such as the ability to create new sounds — that songbirds and other animals share with us. The zebra finch may create new sounds using the same genes as humans, said White, who is also a member of UCLA’s Brain Research Institute.

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Heat-sensitive proteins in different combinations distinguish temperatures, from a warm handshake to spicy foods.

Jie Zheng, UC Davis

The winter sun feels welcome, but not so a summer sunburn. Research over the past 20 years has shown that proteins on the surface of nerve cells enable the body to sense several different temperatures. Now scientists have discovered how just a few of these proteins, called ion channels, distinguish perhaps dozens of discrete temperatures, from mildly warm to very hot.

Researchers showed that the building blocks, or subunits, of heat-sensitive ion channels can assemble in many different combinations, yielding new types of channels, each capable of detecting a different temperature. The discovery, in cell cultures, demonstrates for the first time that only four genes, each encoding one subunit type, can generate dozens of different heat-sensitive channels.

“Researchers in the past have assumed that because there are only four genes, there are only four heat-sensitive channels, but now we have shown that there are many more,” said Jie Zheng, leader of the research and an associate professor of physiology and membrane biology at the UC Davis School of Medicine.

The research publishes today (March 2) in the Journal of Biological Chemistry.

Ion channels are pores in cell membranes. Their ability to open and close controls the flow of charged ions, which turns neuron signalling on or off — in this case to inform the body of the temperature the neuron senses.

The researchers found that when different subunits combine, the resultant hybrid, or heteromeric, channel can detect temperatures about midway between what the “parent” channels detect.

One of the channels they studied, called TRPV1, reacts to hot temperatures — about 100 degrees Fahrenheit. It is also responsible for the ability to sense spicy foods, such as chili peppers. A second channel, TRPV3, responds to temperatures of about 85 degrees. It also senses many food flavors, such as those found in rosemary, oregano, vanilla and cinnamon, that elicit a warm sensation.

When the TRPV1 and TRPV3 subunits recombine, the heteromeric channel is tuned to about 92 degrees. Surprisingly, the study showed that the hybrid channel has an even higher chemical sensitivity than the channels that made it up.

Zheng and his colleagues also showed that channels made up of TRPV1 and TRPV3 subunits react to heat at a rate about midway between that of the two constituent channel subunits. But repeatedly exposing the hybrid channels to their target temperature boosted their response, a behavior called sensitization, which TRPV3 also exhibits.

“It says ‘I remember this temperature. I will make a really loud noise to tell the system that it is coming,’” Zheng said. The process allows the body to be more sensitive to temperature.

By contrast, TRPV1 typically responds the same way when repeatedly exposed to its target temperature — and sometimes even decreases its response, a process called desensitization. It helps the body to adapt to high temperature, Zheng explained.

The research builds on work the team published in 2007 demonstrating that the heat-sensitive subunits can combine to form heteromeric channels. However, at the time, scientists didn’t know how these channels respond to heat. The new work shows that the channels are indeed sensitive to different temperatures.

“Knowing that there are many distinct heat-sensing ion channels now opens the way to understand how neurons encode precise temperature information, an important process that allows us to enjoy the rich spectrum of temperature in life — a memorable warm handshake, a soothing shower and a cup of hot latte — and add vanilla flavor, please,” Zheng said. “It also may provide insights regarding the causes and potential treatments for temperature-sensitivity disorders, such as Raynaud’s syndrome.”

Raynaud’s syndrome is a condition that causes some areas of the body — such as fingers, toes, the tip of the nose and ears — to feel numb and cool in response to cold temperatures or stress. The cause is unknown.

The scientists introduced the genes for TRPV1 and TRPV3 channel subunits to cultured human kidney cells. They tagged the genes with fluorescent markers to confirm when the resulting proteins had combined to form a new channel complex.

Once functional channels were formed, the researchers used a glass pipette with a very fine tip to record ion channels’ responses to temperature changes.

In order to rapidly increase the temperature, they built an apparatus that allowed them to deliver an infrared laser beam to the cell. The method allowed them to heat the channel more than a thousand times faster than commercially available heating devices.

The collaborative research is funded by the National Institutes of Health, the American Heart Association and the Chinese government.

The UC Davis School of Medicine is among the nation’s leading medical schools, recognized for its research and primary-care programs. The school offers fully accredited master’s degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For more information, visit UC Davis School of Medicine at medschool.ucdavis.edu.

UC Davis research reveals how human body keeps essential genes switched “on.”

Frederic Chedin, UC Davis

Researchers at the University of California, Davis, have figured out how the human body keeps essential genes switched “on” and silences the vast stretches of genetic repeats and “junk” DNA.

Frédéric Chédin, associate professor in the Department of Molecular and Cellular Biology, describes the research in a paper published today (March 1) in the journal Molecular Cell. The work could lead to treatments for lupus and other autoimmune diseases, by reversing the gene-silencing process known as cytosine methylation.

“R-loops” are the key, say graduate student Paul Ginno, Chédin and colleagues. The loops emerge in the RNA transcription process in DNA sections that are rich in cytosine and guanine, the C and G in the four-letter DNA code. These C and G stretches serve as “on” switches, or promoters, for about 60 percent of human genes.

Scientists have known since the 1980s that these so-called CG island promoters are not subject to methylation. But, Chédin said, the mechanism has been a long-standing mystery.

The UC Davis researchers built a catalog of almost 8,000 CG islands in the human genome, studied their DNA sequences and found the CG sequences to be skewed toward having one strand of the double helix rich in guanine, and the complementary strand rich in cytosine.

Then, in RNA transcription, the G-rich RNA remains stably bound to a C-rich DNA strand, forcing the G-rich DNA strand into a loop — which then prevents methylation.

DNA methylation is considered part of the new field of epigenetics, which studies inheritable genetic changes that are not directly coded in the DNA sequence. However, the new work shows that, at least at CG islands, the epigenetic state is determined by the DNA sequence.

Scientists know that reduced methylation of DNA plays a key role in triggering autoimmunity in lupus, Chédin said. However, the molecular events behind this DNA under-methylation have been unclear.

“Our work establishes that excessive R-loop formation may drive under-methylation and autoimmunity,” Chédin said.

Co-authors: Paul Lott, graduate student; Holly Christensen, undergraduate; and Ian Korf, associate professor in the Department of Molecular and Cellular Biology and the Genome Center.

The National Institutes of Health and the Foundation for Prader-Willi Research supported the project.

About UC Davis

For more than 100 years, UC Davis has engaged in teaching, research and public service that matter to California and transform the world. Located close to the state capital, UC Davis has more than 32,000 students, more than 2,500 faculty and more than 21,000 staff, an annual research budget that exceeds $684 million, a comprehensive health system and 13 specialized research centers. The university offers interdisciplinary graduate study and more than 100 undergraduate majors in four colleges — Agricultural and Environmental Sciences, Biological Sciences, Engineering, and Letters and Science. It also houses six professional schools — Education, Law, Management, Medicine, Veterinary Medicine and the Betty Irene Moore School of Nursing.

UC Santa Barbara study points to enzyme CysK as potential catalyst.

Christopher Hayes (left) and Christina Beck, UC Santa Barbara

What if bacteria could talk to each other? What if they had a sense of touch? A new study by researchers at UC Santa Barbara suggests both, and theorizes that such cells may, in fact, need to communicate in order to perform certain functions. The findings appear today (March 1) in the journal Genes & Development.

Christopher Hayes, UCSB associate professor of molecular, cellular, and development biology, teamed with graduate students Elie Diner, Christina Beck, and Julia Webb to study uropathogenic E. coli (UPEC), which causes urinary tract infections in humans. They discovered a sibling-like link between cell systems that have largely been thought of as rivals.

The paper shows that bacteria expressing a contact — dependent growth inhibition system (CDI) can inhibit bacteria without such a system only if the target bacteria have CysK, a metabolic enzyme required for synthesis of the amino acid cysteine. CysK is shown to bind to the CDI toxin — an enzyme that breaks RNA ó and activate it.

For a cell system typically thought of as existing only to kill other bacteria — as CDIs have largely been — the results are surprising, said Hayes, because they suggest that a CDI+ inhibitor cell has to get permission from its target in order to do the job.

“This is basically the inhibitor cell asking the target cell, ‘Can I please inhibit you?’” he explained. “It makes no sense. Why add an extra layer of complexity? Why add a permissive factor? That’s an unusual finding.

“We think now that the [CDI] system is not made solely because these cells want to go out and kill other cells,” Hayes continued. “Our results suggest the possibility that these cells may use CDI to communicate as siblings and team up to work together; for example, in formation of a biofilm, which lends bacteria greater strength and better odds of survival.”

The study points to the enzyme CysK as the potential catalyst to such bacterial communication –– like a secret handshake, or a password. In simpler terms, said Hayes, “If you have the right credentials, you’re allowed into the club; otherwise you’re turned away. There’s a velvet rope, if you will, and if you’re not one of the cool kids, you can’t get in.”

Although only UPEC was studied for this paper, Hayes said that the findings hold potential implications for pathogens from bacterial meningitis to the plague, as well as for plant-based bacteria that can devastate vegetation.

David Low, a UCSB professor of molecular, cellular and developmental biology and secondary author on the paper, described the work by Hayes’s laboratory as potentially groundbreaking for its insights into how bacteria communicate — and the practical applications that could someday result.

“We are just starting to get some clues that bacteria may be talking to each other with a contact-dependent language,” said Low. “They touch and respond to one another in different ways depending on the CDI systems and other genotypic factors. Our hope is that ultimately this work may aid the development of drugs that block or enhance touch-dependent communication, whether the bacteria is harmful or helpful.”

The work was supported by grants from the National Institutes of Health and the National Science Foundation.

UC Santa Barbara research pinpoints genes that identify patients with age-related macular degeneration.

Monte Radeke, UC Santa Barbara

Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide, especially in developed countries. There is currently no known cure or treatment for the vast majority of AMD patients.

A new study led by scientists at UC Santa Barbara has identified genes whose expression levels can identify people with AMD, as well as genes that distinguish clinical AMD subtypes. The findings, which appear in BioMed Central’s journal Genome Medicine, could offer new candidate targets for the development of AMD diagnostics and therapies.

It is estimated that 6.5 percent of people over age 40 in the U.S. have AMD. While smoking and UV light exposure are both risk factors for the disease, most of the risk for AMD is heritable. Several genes, including those involved in the innate immune system and fat metabolism, have been associated with altered risk for AMD. However, a detailed molecular description of the disease has yet to emerge.

“In large part, previous studies of AMD have taken a reductionist approach, focusing on one or a handful of genes or gene products at a time,” said Monte Radeke, research scientist with UC Santa Barbara’s Neuroscience Research Institute and one of the project leaders. “We have taken a more holistic approach, directed at characterizing the entire scope of changes associated with AMD. By coupling this with a bioinformatic-driven analysis we can assemble a detailed, testable model that explains AMD.”

Researchers at UC Santa Barbara, the University of Utah’s John Moran Eye Center, and the University of Iowa combined forces to tackle the issue. Tissue samples from a human donor eye repository were used to identify genes up-regulated in AMD. The ability of these genes to recognize AMD was tested on a separate set of samples obtained from the Lions Eye Bank of Oregon.

The team led by UC Santa Barbara scientists discovered hundreds of genes with altered levels in AMD, the top 20 of which were able to predict a clinical AMD diagnosis. Genes over-expressed in the RPE-choroid (a tissue complex located beneath the retina) include components of cell-mediated inflammatory responses; while in the retina, the researchers found genes that function in wound healing and the complement cascade, a part of the innate immune system previously linked to AMD.

In donors with advanced stages of AMD, the researchers found extensive gene networks associated with neovascular AMD (in which the growth of new blood vessels obliterates the retina) and geographic atrophy (where the photoreceptors and RPE waste away). Consistent with the loss of vision in these advanced AMD stages, they found a decreased expression of a number of genes responsible for the detection of light.

Radeke explained: “Not only are these genes able to identify people with clinically recognized AMD and distinguish between different advanced types, some of these genes appear to be associated with pre-clinical stages of AMD. This suggests that they may be involved in key processes that drive the disease. Now that we know the identity and function of many of the genes involved in the disease, we can start to look among them to develop new diagnostic methods, and for new targets for the development of treatments for all forms of AMD.”

Campus joins with China-based genomic organization to form BGI@UC Davis partnership.

Ralph Hexter, UC Davis

The University of California, Davis, and China-based BGI, the world’s largest genomics organization, based in China, signed a master agreement today (Feb. 17) sealing a partnership that will change the landscape of genomic sciences in California and the Western states by establishing a joint facility called BGI@UC Davis. The alliance will foster critical breakthroughs in the areas of food security and human, animal and environmental health.

The master agreement was signed today by UC Davis Provost Ralph G. Hexter and Hao Zhang, co-director of BGI@UC Davis, at a morning ceremony in Los Angeles, with high-ranking dignitaries from China and the United States attending.

“Today marks an exciting new chapter in the collaboration between UC Davis, with our exceptional strengths in biology, medicine, food and the environment, and BGI, the world’s premier genomics organization,” said UC Davis Chancellor Linda P.B. Katehi. “The discoveries that flow from this partnership will have a worldwide impact.”

Under the agreement, UC Davis faculty and students will expand access to the capabilities and expertise of one of the world’s premier genomics and bioinformatics institutes, while BGI researchers will be able to access the university’s diverse resources and expertise in research, especially in biology, human and veterinary medicine, agriculture, the environment and education.

Jian Wang, president of BGI, stated, “We look forward to a highly productive relationship with UC Davis, one of the top research universities in the U.S., especially in the areas of agricultural, environmental and biological research. Given UC Davis’ expertise in these areas, coupled with BGI’s expertise in genome sequencing and bioinformatics, we expect this partnership and the establishment of BGI@UC Davis to lead to significant scientific breakthroughs.”

In June of 2011, Katehi and Wang signed the initial agreement to establish the BGI@UC Davis partnership during a meeting in Shenzhen, one of China’s Special Economic Zones.

This was followed by a second agreement signed in October 2011 that established an interim BGI facility for immediate use at the UC Davis School of Medicine in Sacramento and initiated planning for a permanent BGI@UC Davis facility. That signing ceremony, held in Sacramento for this second agreement, was attended by both Qin Xu, the mayor of Shenzhen, and Kevin Johnson, the mayor of Sacramento.

Under the October 2011 agreement, BGI has moved three state-of-the-art DNA sequencing machines into the interim facility on the UC Davis Sacramento campus. When complete, the facility will accommodate 20 such machines, dramatically increasing the DNA sequencing capacity readily available to campus researchers.

The partnership between BGI and UC Davis will provide new opportunities for researchers at both institutions, said Harris Lewin, vice chancellor for research at UC Davis. It will enable them to tackle bigger and more complex problems and assemble teams that can compete for bigger grants. It will also act as a catalyst to bring new companies and businesses to Sacramento, Lewin said.

The BGI@UC Davis facility will partner with the existing UC Davis Genome Center, located in the Genome and Biomedical Sciences Facility on the UC Davis campus, in the further development of genomics at UC Davis. The new BGI@UC Davis facility will dramatically increase the capacity for sequencing at UC Davis.

Genomics is a discipline of biology concerning the study of the genome, or all the genes of an organism. The field includes intensive efforts to determine the genomes of plants, animals, microbes and other living things, as a way to better understand how they grow, develop and function. Since the first human genome was completed in 2001, the genomes of many other plants and animals have been sequenced, including lab animals and plants, crops such as rice, and disease-causing microbes.

About BGI
BGI was founded in Beijing, China in 1999, with the mission of being a premier scientific partner to the global research community. The goal of BGI is to make leading-edge genomic science highly accessible through its investment in infrastructure that leverages the best available technology, economies of scale and expert bioinformatics resources. BGI and its affiliates, BGI Americas, based in Cambridge, Mass., and BGI Europe, based in Copenhagen, Denmark, have established partnerships and collaborations with leading academic and government research institutions as well as global biotechnology and pharmaceutical companies, supporting a variety of disease, agricultural, environmental and related applications. BGI has established a proven track record of excellence, delivering results with high efficiency and accuracy for innovative, high profile research, which has generated more than 170 publications in top-tier journals such as Nature and Science. These accomplishment include sequencing one percent of the human genome for the International Human Genome Project, contributing 10 percent to the international Human HapMap Project, carrying out research to combat SARS and deadly German E. coli, playing a key role in the Sino-British Chicken Genome Project, and completing the sequence of the rice genome, the silkworm genome, the first Asian diploid genome, the potato genome and, most recently, 1,000 genomes and human gut metagenome. For more information about BGI, please visit www.genomics.cn and www.bgiamericas.com.

About UC Davis
For more than 100 years, UC Davis has engaged in teaching, research and public service that matter to California and transform the world. Located close to the state capital, UC Davis has more than 32,000 students, more than 2,500 faculty and more than 21,000 staff, an annual research budget that exceeds $684 million, a comprehensive health system and 13 specialized research centers. The university offers interdisciplinary graduate study and more than 100 undergraduate majors in four colleges — Agricultural and Environmental Sciences, Biological Sciences, Engineering, and Letters and Science. It also houses six professional schools — Education, Law, Management, Medicine, Veterinary Medicine and the Betty Irene Moore School of Nursing.

Proteins cooperate to regulate gene splicing.

Understanding how RNA binding proteins control the genetic splicing code is fundamental to human biology and disease — much like editing film can change a movie scene. Abnormal variations in splicing are often implicated in cancer and genetic neurodegenerative disorders.

In a step toward deciphering the “splicing code” of the human genome, researchers at the University of California, San Diego, School of Medicine have comprehensively analyzed six of the more highly expressed RNA binding proteins collectively known as heterogeneous nuclear ribonucleoparticle (hnRNP) proteins.

This study, published online today (Feb. 16) in Cell Press’ new open-access journal Cell Reports, describes how multiple RNA binding proteins cooperatively control the diversity of proteins in human cells by regulating the alternative splicing of thousands of genes.

In the splicing process, fragments that do not typically code for protein, called introns, are removed from gene transcripts, and the remaining sequences, called exons, are reconnected. The proteins that bind to RNA are important for the control of the splicing process, and the location where they bind dictates which pieces of the RNA are included or excluded in the final gene transcript — in much the same fashion that removing and inserting scenes, or splicing, can alter the plot of a movie.

“By integrating vast amounts of information about these key binding proteins, and making this data widely available, we hope to provide a foundation for building predictive models for splicing and future studies in other cell types such as embryonic stem cells,” said principal investigator Gene Yeo, Ph.D., assistant professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego, and a visiting professor at the Molecular Engineering Laboratory in Singapore. “If we can understand how these proteins work together and affect one another to regulate alternative splicing, it may offer important clues for rational drug design.”

The data sets highlighted in this study — derived from genome-wide methods including custom-designed splicing-sensitive microarrays, RNA sequencing and high-throughput sequencing to identify genome-wide binding sites (CLIP-seq) — map the functional binding sites for six of the major hnRNP proteins in human cells.

“We identified thousands of binding sites and altered splicing events for these hnRNP proteins and discovered that, surprisingly these proteins bind and regulate each other and a whole network of other RNA binding proteins, suggesting that these proteins are important for the homeostasis of the cell,” said first author, NSF fellow Stephanie C. Huelga.

According to the UC San Diego researchers, the genes specifically targeted by the RNA binding proteins in this study are also often implicated in cancer. Yeo added that of the thousands of genomic mutations that appear in cancer, a vast majority occur in the introns that are removed during splicing; however, intronic regions are where regulatory hnRNP proteins often bind.

“Our findings show an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells. The orchestration of RNA binding proteins is not only important for the homeostasis of the cell, but — by mapping the location of binding sites and all the regulatory places in a gene — this study could reveal how disruption of the process leads to disease and, perhaps, a way to intervene.”

Additional contributors to the study include Anthony Q. Vu, Justin D. Arnold, Tiffany Y. Liang, Patrick P. Liu and Bernice Y. Yan, UC San Diego Cellular and Molecular Medicine; John Paul Donohue, Lily Shiue and Manuel Ares, Jr., UC Santa Cruz; Shawn Hoon and Sydney Brenner, A*STAR, Singapore.

The study was funded in part by grants from the National Institutes of Health and the UC San Diego Stem Cell Research Program.

How zygotes sort out imprinted genes.

A five-day-old human blastocyst

Writing in the Feb. 17 issue of the journal Cell, researchers at the Ludwig Institute for Cancer Research, the University of California, San Diego, School of Medicine and the Toronto Western Research Institute peel away some of the enduring mystery of how zygotes or fertilized eggs determine which copies of parental genes will be used or ignored.

In developing humans and other mammals, not all genes are created equal – or equally used. The expression of certain genes, known as imprinted genes, is determined by just one copy of the parents’ genetic contribution. In humans, there are at least 80 known imprinted genes. If a copy of an imprinted gene fails to function correctly – or if both copies are expressed – the result can be a variety of heritable conditions, such as Prader-Willi and Angelman syndromes, or diseases like cancer.

In the Cell paper, a team of scientists, led by Bing Ren, Ph.D., head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research at UC San Diego, describe in greater detail how differential DNA methylation in the two parental genomes set the stage for selective expression of imprinted genes in the mouse. Differential DNA methylation is essential to normal development in humans and other higher organisms. It involves the addition of hydrocarbon compounds called methyls to cytosine, one of the four bases or building blocks of DNA. Such addition alters the expression of different genes, boosting or suppressing them to help direct embryonic growth and development.

The process is sometimes called epigenetic regulation. Epigenetics is the study of factors influencing inheritance beyond the genes themselves. “DNA is just half the story,” said Ren, who also heads the San Diego Epigenome Center, one of four centers established by the National Institutes of Health to focus on epigenetics research.

“Understanding how these limited imprinted regions control regulation can help us better understand how certain diseases happen,” said Ren, a professor of cellular and molecular medicine in the UC San Diego School of Medicine. “That can help us develop better diagnostic tools for detecting genetic abnormalities and perhaps learn how to predict whether something bad will happen.”

Using a deep sequencing, high-throughput screening technology developed by Joseph Ecker at the Salk Institute for Biological Studies, Ren and colleagues found parent-of-origin specific DNA methylation imprints at 1,952 dinucleotide sequences in the mouse genome. The imprinted sequences formed 55 discrete clusters that included virtually all of the known germline differentially methylated regions and 23 previously unknown regions.

“That suggests it’s a very accurate tool,” said Wei Xie, first author of the paper and a postdoctoral researcher in Ren’s laboratory.

The researchers also found a unique type of methylation in the brain that was previously only seen in embryonic cells. “At this point we do not know what the significance of this modification is in the brain, but it is very specific, suggesting that it correlates to an important biological function” said Cathy L. Barr, PhD, a senior scientist at the Toronto Western Research Institute, the Hospital for Sick Children and co-author of the paper.

Funding for this research came, in part, from the Krembil Seed Development Fund, an Applied Biosystems (Life Technologies) 10K Genome award, the Ludwig Institute for Cancer Research, the NIH Epigenomics Roadmap Project and the National Human Genome Research Institute.

Co-authors are Audrey Kim, Feng Yue and Ah Young Lee, Ludwig Institute for Cancer Research; James Eubanks, Toronto Western Research Institute, Toronto; and Emma L. Dempster, Toronto Western Research Institute, Toronto and Institute of Psychiatry, Kings College London.

UC Davis study highlights the interaction between epigenetics and genetics and exposure to a flame retardant in mice.

Rima Woods (left) and Janine LaSalle, UC Davis

Mice genetically engineered to be susceptible to autism-like behaviors that were exposed to a common flame retardant were less fertile and their offspring were smaller, less sociable and demonstrated marked deficits in learning and long-term memory when compared with the offspring of normal unexposed mice, a study by researchers at UC Davis has found. The researchers said the study is the first to link genetics and epigenetics with exposure to a flame retardant chemical.

The research was published online today (Feb. 16) in the journal Human Molecular Genetics. It will be presented during a symposium on Saturday (Feb. 18) at the annual meeting of the American Association for the Advancement of Science (AAAS) by Janine LaSalle, a professor in the Department of Medical Microbiology and Immunology in the UC Davis School of Medicine and the UC Davis Genome Center. (LaSalle will discuss her research during a news briefing with her colleagues at 9 a.m. Sunday (Feb. 19) in room 221 on the second level of the Vancouver Convention Center).

“This study highlights the interaction between epigenetics and the effects of early exposure to flame retardants,” said LaSalle, the study’s senior author and a researcher affiliated with the UC Davis MIND Institute. “Our experiments with wild-type and mutant mice indicate that exposure to flame retardants presents an independent risk of neurodevelopmental deficits associated with reduced sociability and learning.”

Epigenetics describes the heritable changes in gene expression caused by mechanisms other than those in the DNA sequence. One such mechanism is DNA methylation, in which genes are silenced when their activation no longer is required. DNA methylation is essential for normal development. The researchers chose a mouse that was genetically and epigenetically susceptible to social behavioral deficits in order to understand the potential effect of this environmental pollutant on genetically susceptible humans.

LaSalle and her colleagues examined the effects of the chemical BDE-47 (Tetrabromodiphenl ether), a member of the class of flame retardants called polybrominated diphenylethers, or PBDEs. PBDEs have been used in a wide range of products, including electronics, bedding, carpeting and furniture. They have been shown to persist in the environment and accumulate in living organisms, and toxicological testing has found that they may cause liver toxicity, thyroid toxicity and neurodevelopmental toxicity, according to U.S. Environmental Protection Agency. BDE-47 is the PBDE found at highest concentrations in human blood and breast milk, raising concerns about its potential neurotoxic effects during pregnancy and neonatal development.

The research was conducted in the offspring of mice genetically engineered for the autism phenotype found in Rett syndrome, a disorder that occurs primarily in females and causes regression in expressive language, motor skills and social reciprocity in late infancy. The condition affects about 1 in 10,000 children.

Autism spectrum disorders are a group of neurodevelopmental disabilities that can cause significant social, communication and behavioral deficits. The U.S. Centers for Disease Control and Prevention estimates that an average of 1 in 110 children born in the United States today will be diagnosed with an autism spectrum disorder.

Rett syndrome is causally linked to defects in the methyl-CpG-binding protein 2 gene MECP2 situated on the X chromosome. Mutations in MECP2 result in a nonfunctional MeCP2 protein, which is required for normal brain development. The researchers evaluated the effects of exposure to BDE-47 on mice genetically engineered to have mutations in MECP2 and their offspring, or pups. The genetically engineered Mecp2 mother mice, or dams, were bred with non-mutant wild-type males. The dams were monitored for 10 weeks — for four weeks prior to conception, three weeks during gestation and three weeks of lactation. They were then compared with a control group of normal, unexposed dams and pups over several generations and hundreds of mice.

The study found that that the weights of the pups of the lactating BDE-47-exposed dams were diminished when compared with the controls, as were their survival rates. To assess the effects of the flame retardant exposure on the pups and their genotypes, the researchers placed them through more than 10 cognitive, social and physical tests.

Female offspring of dams exposed with BDE-47 spent half as much time interacting with another mouse in a 10-minute sociability test compared to controls. The reduced sociability in BDE-47 exposed females corresponded to reduced DNA methylation in females regardless of genotype. In addition, genetic and environmental interaction effects in this study were specifically observed in females.

In a short-term memory test of social novelty, although all mice showed the expected preference for interacting with a novel over a familiar mouse, BDE-47-exposed mutant female mice spent about half as much time interacting with the familiar mouse than their non-mutant littermates. In a long-term memory test of swimming to reach a hidden platform in a cloudy pool, female mice who were both mutant and BDE-47 exposed did not learn to reach the platform faster after fourdays of training. These behavioral changes in social and cognitive learning specifically in the interaction group corresponded to changes in a known epigenetic regulator of DNA methylation in brain, DNA methyltransferase 3a (Dnmt3a).

LaSalle said that the study results are important because better understanding of the epigenetic pathways implicated in social behavior and cognition may lead to improved treatments for autism spectrum disorders.

“While the obvious preventative step is to limit the use and accumulation of PBDEs in our environment, this would likely be a long-term solution,” LaSalle said. “These pollutants are going to be hard to get rid of tomorrow. However, one important preventative that all women could do tomorrow is to start taking prenatal vitamins before becoming pregnant, as these may counteract the toxins in our environment through DNA methylation,” she said.

A study by researchers at UC Davis conducted in 2011 found that women who reported not taking a daily prenatal vitamin immediately before and during the first month of pregnancy were nearly twice as likely to have a child with an autism spectrum disorder as women who did take the supplements — and the associated risk rose to seven times as great when combined with a high-risk genetic make-up.

Other authors of the research are Rima Woods, Roxanne O. Vallero, Mari Golub, Joanne K. Suarez, Tram Anh Ta, Dag H. Yasui, Lai-Har Chi, Isaac N. Pessah and Robert F. Berman, all of UC Davis, and Paul J. Kostyniak of the Toxicology Research Center, University at Buffalo, the State University of New York.

The research was funded by grants from the National Institutes of Health and the American Recovery and Reinvestment Act, the National Institutes of Environmental Health Sciences/Environmental Protection Agency Center for Children’s Environmental Health, and the U.S. Environmental Protection Agency Science to Achieve Results (STAR) program.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.

School of Medicine retreat focuses on applications in research, patient care and education.

(From left) Joseph DeRisi, Clay Johnston, Sam Hawgood, UC San Francisco

In the world of bioinformatics, the rush is on to extract gold from a data mine.

The amount of data that health care providers and scientists collect from patients and research participants is growing explosively. This information ranges from the genetic to laboratory tests and imaging exams, to medical histories and information about treatment and outcomes — and in some cases to survey data on large populations.

This deluge of data and the bioinformatics capabilities necessary to take advantage of it were the focus of this year’s daylong UC San Francisco School of Medicine leadership retreat on Jan. 20. In his welcome address, Dean Sam Hawgood, M.B.B.S., outlined his goal for the day — to engage campus leaders in the question of how to optimally develop, organize and integrate clinical-outcome data, research data, business intelligence, and population data so that information is accessible and usable to empower research and improve medical practice.

Making greater use of available data to improve care

Some have compared efforts to take advantage of the data to trying to drink from a fire hose. Consider DNA as an example. Our genetic variations contain clues to disease risk, disease prognosis and treatment response. The identification of such clues by scientists and their translation into medical practice is a major enterprise. Soon, expense will no longer be a major limitation to obtaining a readout of an individual’s entire genetic makeup. “A complete human genome assay will be an assay like any other, at least in terms of cost and time,” Hawgood said.

However, as vivid as the water hose analogy may be, it might be more apt to say that in many organizations data of many types dwells in various unconnected dammed reservoirs, with little of it flowing to potential users.

Much of the day’s discussions centered not only on identifying data to collect and on ways to use this data, but also on how best to “unlock the data” that already exists.

In introducing the day’s theme, Hawgood said that in his view, UCSF, despite the depth and range of clinical and research data being collected, must develop ways to make much greater use of available data in the day-to-day workflow to improve research and patient care.

UCSF’s leaders in informatics can learn from what others have already done. “We want to take enough time to make sure that we’re not repeating other people’s mistakes,” Hawgood said.

Already this year UCSF is completing implementation of a new electronic medical records system, called APeX, tailored to UCSF by EPIC Systems Corp. of Madison, Wis. The system features a single, comprehensive record for each patient.

Apart from being a boon to physicians and other care providers, information within the new clinical record can be “de-identified” to protect privacy and then made available to researchers.

The experience gained from the implementation and the system itself may be a good jumping off point for using data to advance research and education. But the true potential of APeX as a platform to support collaborative research is still being investigated. Taking full advantage of UCSF medical records for research — and enabling ways for new research findings to be used to better guide patient care — will require new innovations.

UCSF already has convened a task force, soliciting input from an external team of international leaders in the field, to explore strategies to bolster bioinformatics on campus, including the establishment of new academic programs and infrastructure through which computer sciences faculty and other bioinformatics experts could be recruited, new experts trained, and novel research collaborations launched. In addition, Hawgood noted, thanks to UCSF’s proximity to Silicon Valley, “We are in a spectacular region for partnerships.”

UCSF is exploring how to accomplish its bioinformatics goals within UCSF and its affiliates, as well as ways in which to access and use data in research networks that span institutions. In addition, there is a need to share information with other providers to provide the best care to patients who also obtain health care outside of UCSF, a theme discussed at last year’s School of Medicine retreat as well.

Using hospital systems as living laboratories

In his keynote address at this year’s retreat, “Aligning the Academic Health Care Enterprise for Acceleration of Precision Medicine,” Isaac Kohane, M.D., Ph.D., a renowned bioinformatics expert and a professor of pediatrics and health sciences and technology at Harvard Medical School, said that the expense of working with data from clinical records has historically been much more expensive than working with genetic and molecular laboratory data.

Kohane, who co-directs the Harvard Medical School Center for Biomedical Informatics, has led efforts to develop computer systems to allow cheaper use of clinical records data from multiple hospital data systems in the study of genes and disease, while maintaining privacy.

Kohane talked about the potential for “apps” to capture useful information related to health outside of the hospital or clinic — for instance a tool that tallies nutritional information on purchases from the cash register.

In his own research Kohane now combines clinical and genomic data to learn more about cancer and autism, but he also presented research showing that such systems — had they been in place earlier — could have called attention to serious side effects of Vioxx and other drugs much sooner.

Kohane’s described workflows and systems that can better “unlock” clinical data to speed research discovery and its application in medical practice, while lowering the costs of using clinical data.

Imagining UCSF’s future in the Digital Age

Speakers at a morning panel titled “Imagining UCSF’s Future in the Age of Information Technology,” included Opinder Bawa, chief technology officer for the School of Medicine; Michael Blum, M.D., medical director of information technology for the UCSF Medical Center; Catherine Lucey, M.D., vice dean for education; Joe DeRisi, Ph.D., co-chair of the Department of Biochemistry and Biophysics; and moderator Clay Johnston, M.D., Ph.D., director of the Clinical and Translational Science Institute at UCSF and vice chancellor for research.

Not all bioinformatics applications are orchestrated institution-wide from the top down. Panelists and commenters from the audience highlighted a role for applications developed by smaller groups. For instance, as an educational tool, UCSF faculty from the Department of Emergency Medicine have spearheaded implementation of software used by physicians-in-training to respond to simulated clinical scenarios unfolding in real time.

The data collected during these exercises can be used to better understand how long it is likely to take for emergency room physicians to take critical actions — in the management of chest pain or in the ordering of pain medication, for example. In essence, the data can be used to learn more about how we learn, knowledge that can be incorporated into successive generations of teaching tools.

In the coming years, physicians will be trained to become increasingly comfortable using improved, data-driven, decision-making software tools, according to Lucey. “We will be able to teach students how to learn for themselves for 30 to 40 years, and we will free faculty up to teach in person what needs to be taught in person.”

DeRisi described how information on UCSF graduate school applicants is being used to identify factors associated with future success. In addition, he described how extensive data collection is being used to log graduate students’ progress and decision-making throughout their careers —  another way of identifying early career paths that bode well for future success. DeRisi also talked about an information-technology partnership that allows lab notebook entries made on pad devices to be immediately incorporated into a computerized database.

Developing more innovative research, clinical protocols

An afternoon panel — “The Future Is Now” — moderated by Robert Hiatt, M.D., Ph.D., co-chair of the Department of Epidemiology and Biostatistics and deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center, focused on two large-scale collaborative research programs co-led by UCSF researchers in which molecular, clinical and demographic data already are being put to work to develop more innovative research and clinical protocols.

Laura van’t Veer, Ph.D., leader, and Laura Esserman, M.D., co-leader of the cancer center’s breast oncology program, described the ATHENA Breast Health Project, which unites UC academic medical centers in a state-wide collaboration. The project will initially involve 150,000 women throughout California who will be screened for breast cancer and followed for decades.

ATHENA project leaders aim to create common systems to integrate clinical research and care across the UC campuses to advance the science of prevention, screening, diagnosis, and treatment of breast cancer. The collaborators are creating a biospecimen repository that has broad racial and ethnic representation. A major goal is to marshal molecular and clinical data to better personalize breast care, tailoring treatment to the patient and avoiding overtreatment, and to use the information gained to drive innovation in prevention, diagnosis and treatment.

Neil Risch, Ph.D., co-chair of the Department of Epidemiology and Biostatistics at UCSF and director of the UCSF Institute for Human Genetics, along with Catherine Schaefer, Ph.D., director of the Kaiser Permanente Research Program on Genes Environment and Health, described progress to date in building the largest data base of its kind to focus on genetic variation and environmental exposures in an older population.

The average age of the hundreds of thousands of individuals whose genetic information will be genotyped for the project is 65. The project’s foundation is Kaiser’s electronic health record, which for many Kaiser Permanente members has information spanning decades — including information on clinical diagnosis and treatment as well as lab-test results and prescription information. UCSF expertise has allowed extraordinarily fast genotyping, as well as uniquely large-scale analysis of telomeres to quickly grow the molecular component of the data resource.

The afternoon panel provided a useful point of reference for break-out groups that met afterward, charged with identifying institutional priorities, problems and potential solutions in advancing the use of bioinformatics in research, clinical care and education.

For instance, the ATHENA collaborators have standardized protocols used at the different medical centers, including protocols for mammography screening. To make clinical data more useful for research, some breakout session panelists advocated more extensive standardization of clinical imaging and clinical lab protocols and reporting throughout UCSF clinical practices.

The Kaiser-UCSF collaboration highlights ways to combine strengths across organizations. While Kaiser is famous as a health maintenance organization, UCSF is perhaps best known as a tertiary care center. Some breakout session panelists raised the question — also raised at last year’s retreat — of whether or not the focus of UCSF research should more closely reflect the patient population seen at UCSF and its affiliated medical centers. UCSF specialists routinely gather extensive information on large numbers of patients with serious acute and chronic conditions, including many of the most difficult–to-treat cases. This extensive data is a potential gold mine for research aimed at identifying factors related to disease risk, prognosis and treatment outcomes.

Moving toward a new taxonomy of disease

The retreat followed on the heels of a similarly themed report by the National Academy of Sciences (NAS), “Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease” [PDF] by a committee co-led by UCSF Chancellor Susan Desmond-Hellmann, M.D., M.P.H. The NAS committee advocated the creation of a “knowledge network” that could link researchers in collaborations that span the nation and globe.

The NAS panel envisioned a future in which there is much greater use of genomic and other molecular data to improve and refine the classification of diseases, but also recognized an opportunity to improve research by more extensively taking into account information about how patients fare in the clinic or hospital.

Instead of the current state of affairs, through which biological, pre-clinical and clinical research eventually lead to advances in medical practice, the new paradigm will be a virtuous cycle through which — with appropriate privacy protections — patient data also will feed back into research. In patient care increasing amounts of laboratory information will become available and interpretable more quickly to help teams of caregivers make more accurate and effective decisions and choices in diagnosis, prognosis and treatment for each individual patient.

Newly discovered gene mutations associated with Joubert syndrome, a rare form of autism.

Image using an electron microscope shows a cilium growing from a neuron

A team led by researchers at the University of California, San Diego, School of Medicine reports that newly discovered mutations in an evolved assembly of genes cause Joubert syndrome, a form of syndromic autism.

The findings are published in today’s (Jan. 26) online issue of Science Express.

Joubert syndrome is a rare, recessive brain condition characterized by malformation or underdevelopment of the cerebellum and brainstem. The disease is due specifically to alterations in cellular primary cilia — antenna-like structures found on most cells. The consequence is a range of distinct physical and cognitive disabilities, including poor muscle control and mental retardation. Up to 40 percent of Joubert syndrome patients meet clinical criteria for autism, as well as other neurocognitive disorders, so it is considered a syndromic form of autism.

The cause or causes of Joubert syndrome are not well-understood. Researchers looked at mutations in the TMEM216 gene, which had previously been linked to the syndrome. However, only half of the expected Joubert syndrome patients exhibit TMEM216 gene mutations; the other half did not. Using genomic sequencing, the research team, led by Joseph G. Gleeson, M.D., professor of neurosciences and pediatrics at UC San Diego, broadened their inquiry and discovered a second culprit: mutations in a neighboring gene called TMEM138.

“It is extraordinarily rare for two adjacent genes to cause the same human disease,” said Gleeson. “The mystery that emerged from this was whether these two adjacent, non-duplicated genes causing indistinguishable disease have functional connections at the gene or protein level.”

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DNA mutation found to disrupt cellular function in patients with acute myeloid leukemia.

Norbert Reich, UC Santa Barbara

Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry.

The UC Santa Barbara research team described how a certain mutation in DNA disrupts cellular function in patients with acute myeloid leukemia (AML). The researchers were prompted to study this process by another research team’s discovery that AML patients have a mutation in a certain enzyme, which was reported in the New England Journal of Medicine. The enzyme is a protein called DNMT3A, which leads to changes in how the DNA of AML patients is methylated, or “tagged.” Norbert Reich, professor in the Department of Chemistry and Biochemistry at UC Santa Barbara, was already studying that particular enzyme with his research group, so they began to study the disease process of AML at the cellular level.

Reich explained that tagging is a way of reading DNA at the cellular level. This falls within an area of study called epigenetics, a process that occurs “on top” of genetics. Each person has approximately 200 types of cells, all with the same DNA, and these must be controlled in different ways. “There is an enzyme — a protein — that tags DNA and controls which of the genes in your cells, your DNA, gets turned on and off,” said Reich. “So you have 20,000 genes, and you have to control them differently in your brain than in your liver.”

Reich explained that there is current interest in this broader field of epigenetics as a direction for the treatment of cancer. “There’s definitely the idea that this may be a new way of developing therapeutics, because you don’t have to kill the cancer cell,” said Reich. “Almost every cancer therapy that’s out there works on the principle that a cancer cell needs to be killed.”

With epigenetics, instead of only having DNA sequence coding for certain genes, there is an epigenetic process, with another layer of information on top of the genetic process. In this case, that information is the tagging by the methyl groups.

“If you really think about it, this is part of the answer as to how your cells can be so different and yet they all have the same DNA,” said Reich. “You have the same genome in every one of your cells, but you do not have the same epigenome, which is basically the methylation pattern, the tagging pattern. That is different in every type of your cells. And the way this relates back to cancer, with leukemia, in those patients, the tagging is messed up. The patterns are not correct. Our big contribution to that is we’ve explained how the mutations in the enzyme could lead to that disruption of the tagging pattern.”

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