Mindful Discoveries

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Schizophrenia and the Synapse

Genetic evidence suggests that overactive synaptic pruning drives development of schizophrenia.

By Ruth Williams | January 27, 2016 … more follows)

http://www.the-scientist.com/?articles.view/articleNo/45189/title/Schizophrenia-and-the-Synapse/

3.2.4   Mindful Discoveries, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

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C4 (green) at synapses of human neurons

Compared to the brains of healthy individuals, those of people with schizophrenia have higher expression of a gene called C4, according to a paper published inNature today (January 27). The gene encodes an immune protein that moonlights in the brain as an eradicator of unwanted neural connections (synapses). The findings, which suggest increased synaptic pruning is a feature of the disease, are a direct extension of genome-wide association studies (GWASs) that pointed to the major histocompatibility (MHC) locus as a key region associated with schizophrenia risk.

“The MHC [locus] is the first and the strongest genetic association for schizophrenia, but many people have said this finding is not useful,” said psychiatric geneticist Patrick Sullivan of the University of North Carolina School of Medicine who was not involved in the study. “The value of [the present study is] to show that not only is it useful, but it opens up new and extremely interesting ideas about the biology and therapeutics of schizophrenia.”

Schizophrenia has a strong genetic component—it runs in families—yet, because of the complex nature of the condition, no specific genes or mutations have been identified. The pathological processes driving the disease remain a mystery.

Researchers have turned to GWASs in the hope of finding specific genetic variations associated with schizophrenia, but even these have not provided clear candidates.

“There are some instances where genome-wide association will literally hit one base [in the DNA],” explained Sullivan. While a 2014 schizophrenia GWAS highlighted the MHC locus on chromosome 6 as a strong risk area, the association spanned hundreds of possible genes and did not reveal specific nucleotide changes. In short, any hope of pinpointing the MHC association was going to be “really challenging,” said geneticist Steve McCarroll of Harvard who led the new study.

Nevertheless, McCarroll and colleagues zeroed in on the particular region of the MHC with the highest GWAS score—the C4 gene—and set about examining how the area’s structural architecture varied in patients and healthy people.

Schizophrenia: From genetics to physiology at last

Ryan S. Dhindsa, & David B. Goldstein

• Affiliations
• Corresponding authors

Nature (2016)  http://dx.doi.org://10.1038/nature16874

http://www.nytimes.com/2016/01/28/health/schizophrenia-cause-synaptic-pruning-brain-psychiatry.html

Suspect gene may trigger runaway synaptic pruning during adolescence — NIH-funded study

NIH/NATIONAL INSTITUTE OF MENTAL HEALTH

http://media.eurekalert.org/multimedia_prod/pub/web/107629_web.jpg

Versions of a gene linked to schizophrenia may trigger runaway pruning of the teenage brain’s still-maturing communications infrastructure, NIH-funded researchers have discovered. People with the illness show fewer such connections between neurons, or synapses. The gene switched on more in people with the suspect versions, who faced a higher risk of developing the disorder, characterized by hallucinations, delusions and impaired thinking and emotions.

“Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” explained Thomas Lehner, Ph.D., director of the Office of Genomics Research Coordination of the NIH’s National Institute of Mental Health (NIMH), which co-funded the study along with the Stanley Center for Psychiatric Research at the Broad Institute and other NIH components. “It could help explain schizophrenia’s delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain’s working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”

The gene, called C4 (complement component 4), sits in by far the tallest tower on schizophrenia’s genomic “skyline” (see graph below) of more than 100 chromosomal sites harboring known genetic risk for the disorder. Affecting about 1 percent of the population, schizophrenia is known to be as much as 90 percent heritable, yet discovering how specific genes work to confer risk has proven elusive, until now.

A team of scientists led by Steve McCarroll, Ph.D., of the Broad Institute and Harvard Medical School, Boston, leveraged the statistical power conferred by analyzing the genomes of 65,000 people, 700 postmortem brains, and the precision of mouse genetic engineering to discover the secrets of schizophrenia’s strongest known genetic risk. C4’s role represents the most compelling evidence, to date, linking specific gene versions to a biological process that could cause at least some cases of the illness.

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” said McCarroll. “The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that block box, peering inside and starting to see actual biological mechanisms.”

McCarroll’s team, including Harvard colleagues Beth Stevens, Ph.D., Michael Carroll, Ph.D., and Aswin Sekar, report on their findings online Jan. 27, 2016 in the journal Nature.

A swath of chromosome 6 encompassing several genes known to be involved in immune function emerged as the strongest signal associated with schizophrenia risk in genome-wide analyses by the NIMH-funded Psychiatric Genomics Consortium over the past several years. Yet conventional genetics failed to turn up any specific gene versions there linked to schizophrenia.

To discover how the immune-related site confers risk for the mental disorder, McCarroll’s team mounted a search for “cryptic genetic influences” that might generate “unconventional signals.” C4, a gene with known roles in immunity, emerged as a prime suspect because it is unusually variable across individuals. It is not unusual for people to have different numbers of copies of the gene and distinct DNA sequences that result in the gene working differently.

The researchers dug deeply into the complexities of how such structural variation relates to the gene’s level of expression and how that, in turn, might relate to schizophrenia. They discovered structurally distinct versions that affect expression of two main forms of the gene in the brain. The more a version resulted in expression of one of the forms, called C4A, the more it was associated with schizophrenia. The more a person had the suspect versions, the more C4 switched on and the higher their risk of developing schizophrenia. Moreover, in the human brain, the C4 protein turned out to be most prevalent in the cellular machinery that supports connections between neurons.

Adapting mouse molecular genetics techniques for studying synaptic pruning and C4’s role in immune function, the researchers also discovered a previously unknown role for C4 in brain development. During critical periods of postnatal brain maturation, C4 tags a synapse for pruning by depositing a sister protein in it called C3. Again, the more C4 got switched on, the more synapses got eliminated.

In humans, such streamlining/pruning occurs as the brain develops to full maturity in the late teens/early adulthood – conspicuously corresponding to the age-of-onset of schizophrenia symptoms.

Future treatments designed to suppress excessive levels of pruning by counteracting runaway C4 in at risk individuals might nip in the bud a process that could otherwise develop into psychotic illness, suggest the researchers. And thanks to the head start gained in understanding the role of such complement proteins in immune function, such agents are already in development, they note.

“This study marks a crucial turning point in the fight against mental illness. It changes the game,” added acting NIMH director Bruce Cuthbert, Ph.D. “Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments and even prevention.”

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VIDEO: Opening Schizophrenia’s Black Box https://youtu.be/s0y4equOTLg

Reference: Sekar A, Biala AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K Presumey J Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4.Nature. Jan 27, 2016. DOI: 10.1038/nature16549.

Schizophrenia risk from complex variation of complement component 4

Aswin Sekar, Allison R. Bialas, Heather de Rivera, Avery Davis, Timothy R. Hammond, …., Michael C. Carroll, Beth Stevens & Steven A. McCarroll

Nature(2016)   http://dx.doi.org:/10.1038/nature16549

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

Figure 1: Structural variation of the complement component 4 (C4) gene.

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Gene Study Points Toward Therapies for Common Brain Disorders

University of Edinburgh    http://www.dddmag.com/news/2016/01/gene-study-points-toward-therapies-common-brain-disorders

Scientists have pinpointed the cells that are likely to trigger common brain disorders, including Alzheimer’s disease, Multiple Sclerosis and intellectual disabilities.

It is the first time researchers have been able to identify the particular cell types that malfunction in a wide range of brain diseases.

Scientists say the findings offer a roadmap for the development of new therapies to target the conditions.

The researchers from the University of Edinburgh’s Centre for Clinical Brain Sciences used advanced gene analysis techniques to investigate which genes were switched on in specific types of brain cells.

They then compared this information with genes that are known to be linked to each of the most common brain conditions — Alzheimer’s disease, anxiety disorders, autism, intellectual disability, multiple sclerosis, schizophrenia and epilepsy.

Their findings reveal that for some conditions, the support cells rather than the neurons that transmit messages in the brain are most likely to be the first affected.

Alzheimer’s disease, for example, is characterised by damage to the neurons. Previous efforts to treat the condition have focused on trying to repair this damage.

The study found that a different cell type — called microglial cells — are responsible for triggering Alzheimer’s and that damage to the neurons is a secondary symptom of disease progression.

Researchers say that developing medicines that target microglial cells could offer hope for treating the illness.

The approach could also be used to find new treatment targets for other diseases that have a genetic basis, the researchers say.

Dr Nathan Skene, who carried out the study with Professor Seth Grant, said: “The brain is the most complex organ made up from a tangle of many cell types and sorting out which of these cells go wrong in disease is of critical importance to developing new medicines.”

Professor Seth Grant said: “We are in the midst of scientific revolution where advanced molecular methods are disentangling the Gordian Knot of the brain and completely unexpected new pathways to solving diseases are emerging. There is a pressing need to exploit the remarkable insights from the study.”

Quantitative multimodal multiparametric imaging in Alzheimer’s disease

Qian Zhao, Xueqi Chen, Yun Zhou      Brain Informatics  http://link.springer.com/article/10.1007/s40708-015-0028-9

Quantitative electroencephalographic and neuropsychological investigation of an alternative measure of frontal lobe executive functions: the Figure Trail Making Test

Brain Informatis    http://dx.doi.org:/10.1007/s40708-015-0025-z    http://link.springer.com/article/10.1007/s40708-015-0025-z/fulltext.html

World’s Greatest Literature Reveals Multifractals, Cascades of Consciousness

http://www.scientificcomputing.com/news/2016/01/worlds-greatest-literature-reveals-multifractals-cascades-consciousness

http://www.scientificcomputing.com/sites/scientificcomputing.com/files/Worlds_Greatest_Literature_Reveals_Multifractals_Cascades_of_Consciousness_440.jpg

Multifractal analysis of Finnegan’s Wake by James Joyce. The ideal shape of the graph is virtually indistinguishable from the results for purely mathematical multifractals. The horizontal axis represents the degree of singularity, and the vertical axis shows the spectrum of singularity. Courtesy of IFJ PAN

Arthur Conan Doyle, Charles Dickens, James Joyce, William Shakespeare and JRR Tolkien. Regardless of the language they were working in, some of the world’s greatest writers appear to be, in some respects, constructing fractals. Statistical analysis, however, revealed something even more intriguing. The composition of works from within a particular genre was characterized by the exceptional dynamics of a cascading (avalanche) narrative structure. This type of narrative turns out to be multifractal. That is, fractals of fractals are created.

As far as many bookworms are concerned, advanced equations and graphs are the last things which would hold their interest, but there’s no escape from the math. Physicists from the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ) in Cracow, Poland, performed a detailed statistical analysis of more than one hundred famous works of world literature, written in several languages and representing various literary genres. The books, tested for revealing correlations in variations of sentence length, proved to be governed by the dynamics of a cascade. This means that the construction of these books is, in fact, a fractal. In the case of several works, their mathematical complexity proved to be exceptional, comparable to the structure of complex mathematical objects considered to be multifractal. Interestingly, in the analyzed pool of all the works, one genre turned out to be exceptionally multifractal in nature.

Fractals are self-similar mathematical objects: when we begin to expand one fragment or another, what eventually emerges is a structure that resembles the original object. Typical fractals, especially those widely known as the Sierpinski triangle and the Mandelbrot set, are monofractals, meaning that the pace of enlargement in any place of a fractal is the same, linear: if they at some point were rescaled x number of times to reveal a structure similar to the original, the same increase in another place would also reveal a similar structure.

Multifractals are more highly advanced mathematical structures: fractals of fractals. They arise from fractals ‘interwoven’ with each other in an appropriate manner and in appropriate proportions. Multifractals are not simply the sum of fractals and cannot be divided to return back to their original components, because the way they weave is fractal in nature. The result is that, in order to see a structure similar to the original, different portions of a multifractal need to expand at different rates. A multifractal is, therefore, non-linear in nature.

“Analyses on multiple scales, carried out using fractals, allow us to neatly grasp information on correlations among data at various levels of complexity of tested systems. As a result, they point to the hierarchical organization of phenomena and structures found in nature. So, we can expect natural language, which represents a major evolutionary leap of the natural world, to show such correlations as well. Their existence in literary works, however, had not yet been convincingly documented. Meanwhile, it turned out that, when you look at these works from the proper perspective, these correlations appear to be not only common, but in some works they take on a particularly sophisticated mathematical complexity,” says Professor Stanislaw Drozdz, IFJ PAN, Cracow University of Technology.

The study involved 113 literary works written in English, French, German, Italian, Polish, Russian and Spanish by such famous figures as Honore de Balzac, Arthur Conan Doyle, Julio Cortazar, Charles Dickens, Fyodor Dostoevsky, Alexandre Dumas, Umberto Eco, George Elliot, Victor Hugo, James Joyce, Thomas Mann, Marcel Proust, Wladyslaw Reymont, William Shakespeare, Henryk Sienkiewicz, JRR Tolkien, Leo Tolstoy and Virginia Woolf, among others. The selected works were no less than 5,000 sentences long, in order to ensure statistical reliability.

To convert the texts to numerical sequences, sentence length was measured by the number of words (an alternative method of counting characters in the sentence turned out to have no major impact on the conclusions). The dependences were then searched for in the data — beginning with the simplest, i.e. linear. This is the posited question: if a sentence of a given length is x times longer than the sentences of different lengths, is the same aspect ratio preserved when looking at sentences respectively longer or shorter?

“All of the examined works showed self-similarity in terms of organization of the lengths of sentences. Some were more expressive — here The Ambassadors by Henry James stood out — while others to far less of an extreme, as in the case of the French seventeenth-century romance Artamene ou le Grand Cyrus. However, correlations were evident and, therefore, these texts were the construction of a fractal,” comments Dr. Pawel Oswiecimka (IFJ PAN), who also noted that fractality of a literary text will, in practice, never be as perfect as in the world of mathematics. It is possible to magnify mathematical fractals up to infinity, while the number of sentences in each book is finite and, at a certain stage of scaling, there will always be a cut-off in the form of the end of the dataset.

Things took a particularly interesting turn when physicists from IFJ PAN began tracking non-linear dependence, which in most of the studied works was present to a slight or moderate degree. However, more than a dozen works revealed a very clear multifractal structure, and almost all of these proved to be representative of one genre, that of stream of consciousness. The only exception was the Bible, specifically the Old Testament, which has, so far, never been associated with this literary genre.

“The absolute record in terms of multifractality turned out to be Finnegan’s Wakeby James Joyce. The results of our analysis of this text are virtually indistinguishable from ideal, purely mathematical multifractals,” says Drozdz.

The most multifractal works also included A Heartbreaking Work of Staggering Genius by Dave Eggers, Rayuela by Julio Cortazar, The US Trilogy by John Dos Passos, The Waves by Virginia Woolf, 2666 by Roberto Bolano, and Joyce’sUlysses. At the same time, a lot of works usually regarded as stream of consciousness turned out to show little correlation to multifractality, as it was hardly noticeable in books such as Atlas Shrugged by Ayn Rand and A la recherche du temps perdu by Marcel Proust.

“It is not entirely clear whether stream of consciousness writing actually reveals the deeper qualities of our consciousness, or rather the imagination of the writers. It is hardly surprising that ascribing a work to a particular genre is, for whatever reason, sometimes subjective. We see, moreover, the possibility of an interesting application of our methodology: it may someday help in a more objective assignment of books to one genre or another,” notes Drozdz.

Multifractal analyses of literary texts carried out by the IFJ PAN have been published in Information Sciences, the journal of computer science. The publication has undergone rigorous verification: given the interdisciplinary nature of the subject, editors immediately appointed up to six reviewers.

Citation: “Quantifying origin and character of long-range correlations in narrative texts” S. Drożdż, P. Oświęcimka, A. Kulig, J. Kwapień, K. Bazarnik, I. Grabska-Gradzińska, J. Rybicki, M. Stanuszek; Information Sciences, vol. 331, 32–44, 20 February 2016; DOI: 10.1016/j.ins.2015.10.023

New Quantum Approach to Big Data could make Impossibly Complex Problems Solvable

David L. Chandler, MIT

http://www.scientificcomputing.com/news/2016/01/new-quantum-approach-big-data-could-make-impossibly-complex-problems-solvable

http://www.scientificcomputing.com/sites/scientificcomputing.com/files/New_Quantum_Approach_to_Big_Data_could_make_Impossibly_Complex_Problems_Solvable_440.jpg

This diagram demonstrates the simplified results that can be obtained by using quantum analysis on enormous, complex sets of data. Shown here are the connections between different regions of the brain in a control subject (left) and a subject under the influence of the psychedelic compound psilocybin (right). This demonstrates a dramatic increase in connectivity, which explains some of the drug’s effects (such as “hearing” colors or “seeing” smells). Such an analysis, involving billions of brain cells, would be too complex for conventional techniques, but could be handled easily by the new quantum approach, the researchers say. Courtesy of the researchers

From gene mapping to space exploration, humanity continues to generate ever-larger sets of data — far more information than people can actually process, manage or understand.

Machine learning systems can help researchers deal with this ever-growing flood of information. Some of the most powerful of these analytical tools are based on a strange branch of geometry called topology, which deals with properties that stay the same even when something is bent and stretched every which way.

Such topological systems are especially useful for analyzing the connections in complex networks, such as the internal wiring of the brain, the U.S. power grid, or the global interconnections of the Internet. But even with the most powerful modern supercomputers, such problems remain daunting and impractical to solve. Now, a new approach that would use quantum computers to streamline these problems has been developed by researchers at MIT, the University of Waterloo, and the University of Southern California.

The team describes their theoretical proposal this week in the journal Nature Communications. Seth Lloyd, the paper’s lead author and the Nam P. Suh Professor of Mechanical Engineering, explains that algebraic topology is key to the new method. This approach, he says, helps to reduce the impact of the inevitable distortions that arise every time someone collects data about the real world.

In a topological description, basic features of the data (How many holes does it have? How are the different parts connected?) are considered the same no matter how much they are stretched, compressed, or distorted. Lloyd explains that it is often these fundamental topological attributes “that are important in trying to reconstruct the underlying patterns in the real world that the data are supposed to represent.”

It doesn’t matter what kind of dataset is being analyzed, he says. The topological approach to looking for connections and holes “works whether it’s an actual physical hole, or the data represents a logical argument and there’s a hole in the argument. This will find both kinds of holes.”

Using conventional computers, that approach is too demanding for all but the simplest situations. Topological analysis “represents a crucial way of getting at the significant features of the data, but it’s computationally very expensive,” Lloyd says. “This is where quantum mechanics kicks in.” The new quantum-based approach, he says, could exponentially speed up such calculations.

Lloyd offers an example to illustrate that potential speedup: If you have a dataset with 300 points, a conventional approach to analyzing all the topological features in that system would require “a computer the size of the universe,” he says. That is, it would take 2300 (two to the 300th power) processing units — approximately the number of all the particles in the universe. In other words, the problem is simply not solvable in that way.

“That’s where our algorithm kicks in,” he says. Solving the same problem with the new system, using a quantum computer, would require just 300 quantum bits — and a device this size may be achieved in the next few years, according to Lloyd.

“Our algorithm shows that you don’t need a big quantum computer to kick some serious topological butt,” he says.

There are many important kinds of huge datasets where the quantum-topological approach could be useful, Lloyd says, for example understanding interconnections in the brain. “By applying topological analysis to datasets gleaned by electroencephalography or functional MRI, you can reveal the complex connectivity and topology of the sequences of firing neurons that underlie our thought processes,” he says.

The same approach could be used for analyzing many other kinds of information. “You could apply it to the world’s economy, or to social networks, or almost any system that involves long-range transport of goods or information,” Lloyd says. But the limits of classical computation have prevented such approaches from being applied before.

While this work is theoretical, “experimentalists have already contacted us about trying prototypes,” he says. “You could find the topology of simple structures on a very simple quantum computer. People are trying proof-of-concept experiments.”

Ignacio Cirac, a professor at the Max Planck Institute of Quantum Optics in Munich, Germany, who was not involved in this research, calls it “a very original idea, and I think that it has a great potential.” He adds “I guess that it has to be further developed and adapted to particular problems. In any case, I think that this is top-quality research.”

The team also included Silvano Garnerone of the University of Waterloo in Ontario, Canada, and Paolo Zanardi of the Center for Quantum Information Science and Technology at the University of Southern California. The work was supported by the Army Research Office, Air Force Office of Scientific Research, Defense Advanced Research Projects Agency, Multidisciplinary University Research Initiative of the Office of Naval Research, and the National Science Foundation.

Beyond Chess: Computer Beats Human in Ancient Chinese Game

http://www.rdmag.com/news/2016/01/beyond-chess-computer-beats-human-ancient-chinese-game

http://www.rdmag.com/sites/rdmag.com/files/rd1601_chess.jpg

A player places a black stone while his opponent waits to place a white one as they play Go, a game of strategy, in the Seattle Go Center, Tuesday, April 30, 2002. The game, which originated in China more than 2,500 years ago, involves two players who take turns putting markers on a grid. The object is to surround more area on the board with the markers than one’s opponent, as well as capturing the opponent’s pieces by surrounding them. A paper released Wednesday, Jan. 27, 2016 describes how a computer program has beaten a human master at the complex board game, marking significant advance for development of artificial intelligence. (AP Photo/Cheryl Hatch)

A computer program has beaten a human champion at the ancient Chinese board game Go, marking a significant advance for development of artificial intelligence.

The program had taught itself how to win, and its developers say its learning strategy may someday let computers help solve real-world problems like making medical diagnoses and pursuing scientific research.

The program and its victory are described in a paper released Wednesday by the journal Nature.

Computers previously have surpassed humans for other games, including chess, checkers and backgammon. But among classic games, Go has long been viewed as the most challenging for artificial intelligence to master.

Go, which originated in China more than 2,500 years ago, involves two players who take turns putting markers on a checkerboard-like grid. The object is to surround more area on the board with the markers than one’s opponent, as well as capturing the opponent’s pieces by surrounding them.

While the rules are simple, playing it well is not. It’s “probably the most complex game ever devised by humans,” Dennis Hassabis of Google DeepMind in London, one of the study authors, told reporters Tuesday.

The new program, AlphaGo, defeated the European champion in all five games of a match in October, the Nature paper reports.

In March, AlphaGo will face legendary player Lee Sedol in Seoul, South Korea, for a $1 million prize, Hassabis said.

Martin Mueller, a computing science professor at the University of Alberta in Canada who has worked on Go programs for 30 years but didn’t participate in AlphaGo, said the new program “is really a big step up from everything else we’ve seen…. It’s a very, very impressive piece of work.”

Biological Origin of Schizophrenia

Excessive ‘pruning’ of connections between neurons in brain predisposes to disease

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Imaging studies showed C4 (in green) located at the synapses of primary human neurons. Image: Heather de Rivera, McCarroll lab

 PAUL GOLDSMITH    http://hms.harvard.edu/news/biological-origin-schizophrenia

The risk of schizophrenia increases if a person inherits specific variants in a gene related to “synaptic pruning”—the elimination of connections between neurons—according to a study from Harvard Medical School, the Broad Institute and Boston Children’s Hospital. The findings were based on genetic analysis of nearly 65,000 people.

The study represents the first time that the origin of this psychiatric disease has been causally linked to specific gene variants and a biological process.

Get more HMS news here

It also helps explain two decades-old observations: synaptic pruning is particularly active during adolescence, which is the typical period of onset for symptoms of schizophrenia, and the brains of schizophrenic patients tend to show fewer connections between neurons.

The gene, complement component 4 (C4), plays a well-known role in the immune system. It has now been shown to also play a key role in brain development and schizophrenia risk. The insight may allow future therapeutic strategies to be directed at the disorder’s roots, rather than just its symptoms.

The study, which appears online Jan. 27 in Nature, was led by HMS researchers at the Broad Institute’s Stanley Center for Psychiatric Research and Boston Children’s. They include senior author Steven McCarroll, HMS associate professor of genetics and director of genetics for the Stanley Center; Beth Stevens, HMS assistant professor of neurology at Boston Children’s and institute member at the Broad; Michael Carroll, HMS professor of pediatrics at Boston Children’s; and first author Aswin Sekar, an MD-PhD student at HMS.

The study has the potential to reinvigorate translational research on a debilitating disease. Schizophrenia afflicts approximately 1 percent people worldwide and is characterized by hallucinations, emotional withdrawal and a decline in cognitive function. These symptoms most frequently begin in patients when they are teenagers or young adults.

“These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”

First described more than 130 years ago, schizophrenia lacks highly effective treatments and has seen few biological or medical breakthroughs over the past half-century.

In the summer of 2014, an international consortium led by researchers at the Stanley Center identified more than 100 regions in the human genome that carry risk factors for schizophrenia.

The newly published study now reports the discovery of the specific gene underlying the strongest of these risk factors and links it to a specific biological process in the brain.

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” said McCarroll. “The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside and starting to see actual biological mechanisms.”

“This study marks a crucial turning point in the fight against mental illness,” said Bruce Cuthbert, acting director of the National Institute of Mental Health. “Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between. This study changes the game. Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments and even prevention.”

The path to discovery

The discovery involved the collection of DNA from more than 100,000 people, detailed analysis of complex genetic variation in more than 65,000 human genomes, development of an innovative analytical strategy, examination of postmortem brain samples from hundreds of people and the use of animal models to show that a protein from the immune system also plays a previously unsuspected role in the brain.

Over the past five years, Stanley Center geneticists and collaborators around the world collected more than 100,000 human DNA samples from 30 different countries to locate regions of the human genome harboring genetic variants that increase the risk of schizophrenia. The strongest signal by far was on chromosome 6, in a region of DNA long associated with infectious disease. This caused some observers to suggest that schizophrenia might be triggered by an infectious agent. But researchers had no idea which of the hundreds of genes in the region was actually responsible or how it acted.

Based on analyses of the genetic data, McCarroll and Sekar focused on a region containing the C4 gene. Unlike most genes, C4 has a high degree of structural variability. Different people have different numbers of copies and different types of the gene.

McCarroll and Sekar developed a new molecular technique to characterize the C4 gene structure in human DNA samples. They also measured C4 gene activity in nearly 700 post-mortem brain samples.

They found that the C4 gene structure (DNA) could predict the C4 gene activity (RNA) in each person’s brain. They then used this information to infer C4 gene activity from genome data from 65,000 people with and without schizophrenia.

These data revealed a striking correlation. People who had particular structural forms of the C4 gene showed higher expression of that gene and, in turn, had a higher risk of developing schizophrenia.

Connecting cause and effect through neuroscience

But how exactly does C4—a protein known to mark infectious microbes for destruction by immune cells—affect the risk of schizophrenia?

Answering this question required synthesizing genetics and neurobiology.

Stevens, a recent recipient of a MacArthur Foundation “genius grant,” had found that other complement proteins in the immune system also played a role in brain development. These results came from studying an experimental model of synaptic pruning in the mouse visual system.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics.”

Carroll had long studied C4 for its role in immune disease, and developed mice with different numbers of copies of C4.

The three labs set out to study the role of C4 in the brain.

They found that C4 played a key role in pruning synapses during maturation of the brain. In particular, they found that C4 was necessary for another protein—a complement component called C3—to be deposited onto synapses as a signal that the synapses should be pruned. The data also suggested that the more C4 activity an animal had, the more synapses were eliminated in its brain at a key time in development.

The findings may help explain the longstanding mystery of why the brains of people with schizophrenia tend to have a thinner cerebral cortex (the brain’s outer layer, responsible for many aspects of cognition) with fewer synapses than do brains of unaffected individuals. The work may also help explain why the onset of schizophrenia symptoms tends to occur in late adolescence.

The human brain normally undergoes widespread synapse pruning during adolescence, especially in the cerebral cortex. Excessive synaptic pruning during adolescence and early adulthood, due to increased complement (C4) activity, could lead to the cognitive symptoms seen in schizophrenia.

“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” Stevens said.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics,” she said. “We’re far from having a treatment based on this, but it’s exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk.”

Opening a path toward early detection and potential therapies

Beyond providing the first insights into the biological origins of schizophrenia, the work raises the possibility that therapies might someday be developed that could turn down the level of synaptic pruning in people who show early symptoms of schizophrenia.

This would be a dramatically different approach from current medical therapies, which address only a specific symptom of schizophrenia—psychosis—rather than the disorder’s root causes, and which do not stop cognitive decline or other symptoms of the illness.

The researchers emphasize that therapies based on these findings are still years down the road. Still, the fact that much is already known about the role of complement proteins in the immune system means that researchers can tap into a wealth of existing knowledge to identify possible therapeutic approaches. For example, anticomplement drugs are already under development for treating other diseases.

“In this area of science, our dream has been to find disease mechanisms that lead to new kinds of treatments,” said McCarroll. “These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”

This work was supported by the Broad Institute’s Stanley Center for Psychiatric Research and by the National Institutes of Health (grants U01MH105641, R01MH077139 and T32GM007753).

Adapted from a Broad Institute news release.

Scientists open the ‘black box’ of schizophrenia with dramatic genetic discovery

Amy Ellis Nutt    https://www.washingtonpost.com/news/speaking-of-science/wp/2016/01/27/scientists-open-the-black-box-of-schizophrenia-with-dramatic-genetic-finding/

Scientists Prune Away Schizophrenia’s Hidden Genetic Mechanisms

http://www.genengnews.com/gen-news-highlights/scientists-prune-away-schizophrenia-s-hidden-genetic-mechanisms/81252297/

https://youtu.be/s0y4equOTLg

A landmark study has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in a gene related to “synaptic pruning”—the elimination of connections between neurons. The findings represent the first time that the origin of this devastating psychiatric disease has been causally linked to specific gene variants and a biological process.

http://www.genengnews.com/Media/images/GENHighlight/thumb_107629_web2209513618.jpg

The site in Chromosome 6 harboring the gene C4 towers far above other risk-associated areas on schizophrenia’s genomic “skyline,” marking its strongest known genetic influence. The new study is the first to explain how specific gene versions work biologically to confer schizophrenia risk. [Psychiatric Genomics Consortium]

• A new study by researchers at the Broad Institute’s Stanley Center for Psychiatric Research, Harvard Medical School, and Boston Children’s Hospital genetically analyzed nearly 65,000 people and revealed that an individual’s risk of schizophrenia is increased if they inherited distinct variants in a gene related to “synaptic pruning”—the elimination of connections between neurons. This new data represents the first time that the origin of this psychiatric disease has been causally linked to particular gene variants and a biological process.

The investigators discovered that versions of a gene commonly thought to be involved in immune function might trigger a runaway pruning of an adolescent brain’s still-maturing communications infrastructure. The researchers described a scenario where patients with schizophrenia show fewer such connections between neurons or synapses.

“Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” explained Thomas Lehner, Ph.D., director of the Office of Genomics Research Coordination at the NIH’s National Institute of Mental Health (NIMH), which co-funded the study along with the Stanley Center for Psychiatric Research at the Broad Institute and other NIH components. “It could help explain schizophrenia’s delayed age-of-onset of symptoms in late adolescence and early adulthood and shrinkage of the brain’s working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”

The gene the research team called into question, dubbed C4 (complement component 4), was associated with the largest risk for the disorder. C4’s role represents some of the most compelling evidence, to date, linking specific gene versions to a biological process that could cause at least some cases of the illness.

The findings from this study were published recently in Nature through an article entitled “Schizophrenia risk from complex variation of complement component 4.”

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” noted senior study author Steven McCarroll, Ph.D., director of genetics for the Stanley Center and an associate professor of genetics at Harvard Medical School. “The human genome is providing a powerful new way into this disease. Understanding these genetic effects on risk is a way of prying open that block box, peering inside and starting to see actual biological mechanisms.”

Dr. McCarroll and his colleagues found that a stretch of chromosome 6 encompassing several genes known to be involved in immune function emerged as the strongest signal associated with schizophrenia risk in genome-wide analyses. Yet conventional genetics failed to turn up any specific gene versions there that were linked to schizophrenia.

In order to uncover how the immune-related site confers risk for the mental disorder, the scientists mounted a search for cryptic genetic influences that might generate unconventional signals. C4, a gene with known roles in immunity, emerged as a prime suspect because it is unusually variable across individuals.

Upon further investigation into the complexities of how such structural variation relates to the gene’s level of expression and how that, in turn, might link to schizophrenia, the team discovered structurally distinct versions that affect expression of two main forms of the gene within the brain. The more a version resulted in expression of one of the forms, called C4A, the more it was associated with schizophrenia. The greater number of copies an individual had of the suspect versions, the more C4 switched on and the higher their risk of developing schizophrenia. Furthermore, the C4 protein turned out to be most prevalent within the cellular machinery that supports connections between neurons.

“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” remarked co-author Beth Stevens, Ph.D. a neuroscientist and assistant professor of neurology at Boston Children’s Hospital and institute member at the Broad. “This discovery enriches our understanding of the complement system in brain development and disease, and we could not have made that leap without the genetics. We’re far from having a treatment based on this, but it’s exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk.”

“This study marks a crucial turning point in the fight against mental illness. It changes the game,” added acting NIMH director Bruce Cuthbert, Ph.D. “Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between. This study changes the game. Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments, and even prevention.”

Connecting cause and effect through neuroscience

But how exactly does C4—a protein known to mark infectious microbes for destruction by immune cells—affect the risk of schizophrenia?

Answering this question required synthesizing genetics and neurobiology.

Stevens, a recent recipient of a MacArthur Foundation “genius grant,” had found that other complement proteins in the immune system also played a role in brain development. These results came from studying an experimental model of synaptic pruning in the mouse visual system.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics.”

Carroll had long studied C4 for its role in immune disease, and developed mice with different numbers of copies of C4.

The three labs set out to study the role of C4 in the brain.

They found that C4 played a key role in pruning synapses during maturation of the brain. In particular, they found that C4 was necessary for another protein—a complement component called C3—to be deposited onto synapses as a signal that the synapses should be pruned. The data also suggested that the more C4 activity an animal had, the more synapses were eliminated in its brain at a key time in development.

The findings may help explain the longstanding mystery of why the brains of people with schizophrenia tend to have a thinner cerebral cortex (the brain’s outer layer, responsible for many aspects of cognition) with fewer synapses than do brains of unaffected individuals. The work may also help explain why the onset of schizophrenia symptoms tends to occur in late adolescence.

The human brain normally undergoes widespread synapse pruning during adolescence, especially in the cerebral cortex. Excessive synaptic pruning during adolescence and early adulthood, due to increased complement (C4) activity, could lead to the cognitive symptoms seen in schizophrenia.

“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” Stevens said.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics,” she said. “We’re far from having a treatment based on this, but it’s exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk.”

Opening a path toward early detection and potential therapies

Beyond providing the first insights into the biological origins of schizophrenia, the work raises the possibility that therapies might someday be developed that could turn down the level of synaptic pruning in people who show early symptoms of schizophrenia.

This would be a dramatically different approach from current medical therapies, which address only a specific symptom of schizophrenia—psychosis—rather than the disorder’s root causes, and which do not stop cognitive decline or other symptoms of the illness.

The researchers emphasize that therapies based on these findings are still years down the road. Still, the fact that much is already known about the role of complement proteins in the immune system means that researchers can tap into a wealth of existing knowledge to identify possible therapeutic approaches. For example, anticomplement drugs are already under development for treating other diseases.

“In this area of science, our dream has been to find disease mechanisms that lead to new kinds of treatments,” said McCarroll. “These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”

This work was supported by the Broad Institute’s Stanley Center for Psychiatric Research and by the National Institutes of Health (grants U01MH105641, R01MH077139 and T32GM007753).

Adapted from a Broad Institute news release.

https://img.washingtonpost.com/wp-apps/imrs.php?src=https://img.washingtonpost.com/rf/image_908w/2010-2019/WashingtonPost/2011/09/27/Production/Sunday/SunBiz/Images/mental2b.jpg&w=1484

This post has been updated.

For the first time, scientists have pinned down a molecular process in the brain that helps to trigger schizophrenia. The researchers involved in the landmark study, which was published Wednesday in the journal Nature, say the discovery of this new genetic pathway probably reveals what goes wrong neurologically in a young person diagnosed with the devastating disorder.

The study marks a watershed moment, with the potential for early detection and new treatments that were unthinkable just a year ago, according to Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute at MIT. Hyman, a former director of the National Institute of Mental Health, calls it “the most significant mechanistic study about schizophrenia ever.”

“I’m a crusty, old, curmudgeonly skeptic,” he said. “But I’m almost giddy about these findings.”

The researchers, chiefly from the Broad Institute, Harvard Medical School and Boston Children’s Hospital, found that a person’s risk of schizophrenia is dramatically increased if they inherit variants of a gene important to “synaptic pruning” — the healthy reduction during adolescence of brain cell connections that are no longer needed.

[Schizophrenic patients have different oral bacteria than non-mentally ill individuals]

In patients with schizophrenia, a variation in a single position in the DNA sequence marks too many synapses for removal and that pruning goes out of control. The result is an abnormal loss of gray matter.

The genes involved coat the neurons with “eat-me signals,” said study co-author Beth Stevens, a neuroscientist at Children’s Hospital and Broad. “They are tagging too many synapses. And they’re gobbled up.

The Institute’s founding director, Eric Lander, believes the research represents an astonishing breakthrough. “It’s taking what has been a black box…and letting us peek inside for the first time. And that is amazingly consequential,” he said.

The timeline for this discovery has been relatively fast. In July 2014, Broad researchers published the results of the largest genomic study on the disorder and found more than 100 genetic locations linked to schizophrenia. Based on that research, Harvard and Broad geneticist Steven McCarroll analyzed data from about 29,000 schizophrenia cases, 36,000 controls and 700 post mortem brains. The information was drawn from dozens of studies performed in 22 countries, all of which contribute to the worldwide database called the Psychiatric Genomics Consortium.

[Influential government-appointed panel recommends depression screening for everyone]

One area in particular, when graphed, showed the strongest association. It was dubbed the “Manhattan plot” for its resemblance to New York City’s towering buildings. The highest peak was on chromosome 6, where McCarroll’s team discovered the gene variant. C4 was “a dark corner of the human genome,” he said, an area difficult to decipher because of its “astonishing level” of diversity.

C4 and numerous other genes reside in a region of chromosome 6 involved in the immune system, which clears out pathogens and similar cellular debris from the brain. The study’s researchers found that one of C4’s variants, C4A, was most associated with a risk for schizophrenia.

More than 25 million people around the globe are affected by schizophrenia, according to the World Health Organization, including 2 million to 3 million Americans. Highly hereditable, it is one of the most severe mental illnesses, with an annual economic burden in this country of tens of billions of dollars.

“This paper is really exciting,” said Jacqueline Feldman, associate medical director of the National Alliance on Mental Illness. “We as scientists and physicians have to temper our enthusiasm because we’ve gone down this path before. But this is profoundly interesting.”

There have been hundreds of theories about schizophrenia over the years, but one of the enduring mysteries has been how three prominent findings related to each other: the apparent involvement of immune molecules, the disorder’s typical onset in late adolescence and early adulthood, and the thinning of gray matter seen in autopsies of patients.

[A low-tech way to help treat young schizophrenic patients]

“The thing about this result,” said McCarroll, the lead author, ” it makes a lot of other things understandable. To have a result to connect to these observations and to have a molecule and strong level of genetic evidence from tens of thousands of research participants, I think that combination sets [this study] apart.”

The authors stressed that their findings, which combine basic science with large-scale analysis of genetic studies, depended on an unusual level of cooperation among experts in genetics, molecular biology, developmental neurobiology and immunology.

“This could not have been done five years ago,” said Hyman. “This required the ability to reference a very large dataset . …When I was [NIMH] director, people really resisted collaborating. They were still in the Pharaoh era. They wanted to be buried with their data.”

The study offers a new approach to schizophrenia research, which has been largely stagnant for decades.  Most psychiatric drugs seek to interrupt psychotic thinking, but experts agree that psychosis is just a single symptom — and a late-occurring one at that. One of the chief difficulties for psychiatric researchers, setting them apart from most other medical investigators, is that they can’t cut schizophrenia out of the brain and look at it under a microscope. Nor are there any good animal models.

All that now has changed, according to Stevens. “We now have a strong molecular handle, a pathway and a gene, to develop better models,” he said.

Which isn’t to say a cure is right around the corner.

“This is the first exciting  clue, maybe even the most important we’ll ever have, but it will be decades” before a true cure is found,” Hyman said. “Hope is a wonderful thing. False promise is not.”

Insight Pharma Report

Three neurodegenerative disorders that are heavily focused on in this report include: Alzheimer’s Disease/Mild Cognitive Impairment, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. Part II of the report will include all three of these disorders, highlighting specifics including background, history, and development of the disease. Deeper into the chapters, the report will unfold biomarkers under investigation, genetic targets, and an analysis of multiple studies investigating these elements.

Experts interviewed in these chapters include:

• Dr. Jens Wendland, Head of Neuroscience Genetics, Precision Medicine, Clinical Research, Pfizer Worldwide R&D
• Dr. Howard J. Federoff, Executive Vice President for Health Sciences, Georgetown University
• Dr. Andrew West, Associate Professor of Neurology and Neurobiology and Co-Director, Center for Neurodegeneration and Experimental Therapeutics
• Dr. Merit Ester Cudkowicz, Chief of Neurology at Massachusetts General Hospital

Part III of the report makes a shift from neurobiomarkers to neurodiagnostics. This section highlights several diagnostics in play and in the making from a number of companies, identifying company strategies, research underway, hypotheses, and institution goals. Elite researchers and companies highlighted in this part include:

• Dr. Xuemei Huang, Professor and Vice Chair, Department of Neurology; Professor of Neurosurgery, Radiology,  Pharmacology, and Kinesiology Director; Hershey Brain Analysis Research Laboratory for Neurodegenerative Disorders, Penn State University-Milton, S. Hershey Medical Center Department of Neurology
• Dr. Andreas Jeromin, CSO and President of Atlantic Biomarkers
• Julien Bradley, Senior Director, Sales & Marketing, Quanterix
• Dr. Scott Marshall, Head of Bioanalytics, and Dr. Jared Kohler, Head of Biomarker Statistics, BioStat Solutions, Inc.

Further analysis appears in Part IV. This section includes a survey exclusively conducted for this report. With over 30 figures and graphics and an in depth analysis, this part features insight into targets under investigation, challenges, advantages, and desired features of future diagnostic applications. Furthermore, the survey covers more than just the featured neurodegenerative disorders in this report, expanding to Multiple Sclerosis and Huntington’s Disease.

Finally, Insight Pharma Reports concludes this report with clinical trial and pipeline data featuring targets and products from over 300 companies working in Alzheimer’s Disease, Parkinson’s Disease and Amyotrophic Lateral Sclerosis.

Epigenome Tapped to Understand Rise of Subtype of Brain Medulloblastoma

http://www.genengnews.com/gen-news-highlights/epigenome-tapped-to-understand-rise-of-subtype-of-brain-medulloblastoma/81252294/

Scientists have identified the cells that likely give rise to the brain tumor subtype Group 4 medulloblastoma. [V. Yakobchuk/ Fotolia]

http://www.genengnews.com/Media/images/GENHighlight/thumb_Jan_28_2016_Fotolia_6761569_ColorfulBrain_4412824411.jpg

An international team of scientists say they have identified the cells that likely give rise to the brain tumor subtype Group 4 medulloblastoma. The believe their study (“Active medulloblastoma enhancers reveal subgroup-specific cellular origins”), published in Nature, removes a barrier to developing more effective targeted therapies against the brain tumor’s most common subtype.

Medulloblastoma occurs in infants, children, and adults, but it is the most common malignant pediatric brain tumor. The disease includes four biologically and clinically distinct subtypes, of which Group 4 is the most common. In children, about half of medulloblastoma patients are of the Group 4 subtype. Efforts to improve patient outcomes, particularly for those with high-risk Group 4 medulloblastoma, have been hampered by the lack of accurate animal models.

Evidence from this study suggests Group 4 tumors begin in neural stem cells that are born in a region of the developing cerebellum called the upper rhomic lip (uRL), according to the researchers.

“Pinpointing the cell(s) of origin for Group 4 medulloblastoma will help us to better understand normal cerebellar development and dramatically improve our chances of developing genetically faithful preclinical mouse models. These models are desperately needed for learning more about Group 4 medulloblastoma biology and evaluating rational, molecularly targeted therapies to improve patient outcomes,” said Paul Northcott, Ph.D., an assistant member of the St. Jude department of developmental neurobiology. Dr. Northcott, Stefan Pfister, M.D., of the German Cancer Research Center (DKFZ), and James Bradner, M.D., of Dana-Farber Cancer Institute, are the corresponding authors.

The discovery and other findings about the missteps fueling tumor growth came from studying the epigenome. Researchers used the analytic tool ChiP-seq to identify and track medulloblastoma subtype differences based on the activity of epigenetic regulators, which included proteins known as master regulator transcription factors. They bind to DNA enhancers and super-enhancers. The master regulator transcription factors and super-enhancers work together to regulate the expression of critical genes, such as those responsible for cell identity.

Those and other tools helped investigators identify more than 3,000 super-enhancers in 28 medulloblastoma tumors as well as evidence that the activity of super-enhancers varied by subtype. The super-enhancers switched on known cancer genes, including genes like ALK, MYC, SMO, and OTX2 that are associated with medulloblastoma, the researchers reported.

Knowledge of the subtype super-enhancers led to identification of the transcription factors that regulate their activity. Using computational methods, researchers applied that information to reconstruct the transcription factor networks responsible for medulloblastoma subtype diversity and identity, providing previously unknown insights into the regulatory landscape and transcriptional output of the different medulloblastoma subtypes.

The approach helped to discover and nominate Lmx1A as a master regulator transcription factor of Group 4 tumors, which led to the identification of the likely Group 4 tumor cells of origin. Lmx1A was known to play an important role in normal development of cells in the uRL and cerebellum. Additional studies performed in mice with and without Lmx1A in this study supported uRL cells as the likely source of Group 4 tumors.

“By studying the epigenome, we also identified new pathways and molecular dependencies not apparent in previous gene expression and mutational studies,” explained Dr. Northcott. “The findings open new therapeutic avenues, particularly for the Group 3 and 4 subtypes where patient outcomes are inferior for the majority of affected children.”

For example, researchers identified increased enhancer activity targeting the TGFbeta pathway. The finding adds to evidence that the pathway may drive Group 3 medulloblastoma, currently the subtype with the worst prognosis. The pathway regulates cell growth, cell death, and other functions that are often disrupted in cancer, but it’s role in medulloblastoma is poorly understood.

The analysis included samples from 28 medulloblastoma tumors representing the four subtypes. Researchers believe it is the largest epigenetic study yet for any single cancer type and, importantly, the first to use a large cohort of primary patient tumor tissues instead of cell lines grown in the laboratory. Previous studies have suggested that cell lines may be of limited use for studying the tumor epigenome. The three Group 3 medulloblastoma cell lines used in this study reinforced the observation, highlighting significant differences in epigenetic regulators at work in medulloblastoma cell lines versus tumor samples.

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