Singapore - Cancer biology: Modeling cancer on the fly

Genes that cooperate with known cancer 'drivers' to promote tumor formation in the fruit fly are pointing the way to equivalents in humans.

A study of fruit fly genes reveals how molecules cooperate to induce tumor formation

Cancer biologists have known for decades that even the most potent cancer-causing genes do not act alone. Yet, identifying which combinations of genetic changes can cause a tumor to form and disease to progress remains a challenge. “The hope is that by understanding these [combinations], it will be possible to design therapeutic strategies tailored to the genetic changes in different cancers,” says Stephen Cohen of the A*STAR Institute of Molecular and Cell Biology (IMCB) and the National University of Singapore.

Sequencing the genomes of tumors from cancer patients is one approach to identifying cancer-causing mutations. The number of mutations can be so large, however, that researchers are left wondering which mutations are cancer ‘drivers’ and which are innocuous ‘passengers’, Cohen notes.

Taking an alternative approach, Cohen and his team in Singapore succeeded in identifying cancer-causing genes in the fruit fly, Drosophila melanogaster, based on function1. The team set out to find genes that cooperate with known cancer drivers that promote tumor formation.

They began with a gene linked to breast and lung cancer, epidermal growth factor receptor (EGFR). Team member Hector Herranz developed a fly model in which activation of EGFR caused tissue overgrowth, but these overgrowths did not progress to form tumors. He then screened for secondary genetic changes that would enhance the ability of EGFR to produce tumors. Herranz found that co-expression of a microRNA called bantam with EGFR produced tumors that spread through the body and killed the fly.

As regulatory genes that produce small RNA molecules, microRNAs typically reduce the expression of other genes, decreasing their ability to produce proteins. The team therefore searched for a target of the microRNA whose absence increased the tumor-forming potential of EGFR. Team member Xin Hong was able to locate it: a gene known as Socs36E. In the team’s fly model, Socs36E behaved like a tumor suppressor: the deletion of Socs36E enhanced EGFR-induced tumor formation.

Hong then identified the corresponding human gene as SOCS5. He found that it also behaved as a tumor suppressor; SOCS5 cooperated with EGFR in an experimental model of human cancer.

Studies on human SOCS5 are ongoing, Cohen explains, but early indications point to a breast cancer link. Further work by the team will determine whether SOCS5 could be a useful biomarker.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology, Singapore and the National University of Singapore. The IMCB team collaborated with researchers at Duke NUS Graduate Medical School.

References

1. Herranz, H., Hong, X., Hung, N. T., Voorhoeve, P. M. & Cohen, S. M. Oncogenic cooperation between SOCS family proteins and EGFR identified using a Drosophila epithelial transformation model. Genes & Development26, 1602–1611 (2012). | article

Australia - Crimes Of Evolution: Genes Stolen From Captive Algae

Microscopic animals held algae captive and stole their genes for energy production millions of years ago, reveals a new study.

Microscopic animals held algae captive and stole their genes for energy production millions of years ago, reveals a new study.

The study, published this week in the journal Nature, reveals a ‘missing link’ in evolution, where tiny protozoa frozen in time captured algal genes for photosynthesis – the process of harnessing light to produce energy which is used by all plants and algae on earth.

Until now, the international team led by researchers from Dalhousie University in Canada had suspected that quantum leaps of evolution occurred by one organism cannibalizing another, but had insufficient evidence to prove this hypothesis.

But when they looked at two specific algae – Guillardia theta and Bigelowiella natans – the team realized the evolution was not quite complete. They could see that their cells had two nuclei, which is unusual because plant and animal cells only have one.

“We think that the genes for photosynthesis originally evolved only once about three billion years ago. So all plants, algae, and blue green bacteria can produce their own energy from light because they have acquired these genes for photosynthesis,” said Professor McFadden from the University of Melbourne, a co-author on the study.

Like prisoners in Alcatraz, the captive algae appear to have been nurtured by their enslavers and the precious sugars produced from photosynthesis became a vital part of the protozoan slave keeper’s diet.

The captives lived inside the protozoan cell and, under the right conditions, the pair gradually became unified as a single organism – a process called endosymbiosis, which literally means living inside each other.

“We discovered that the captors were initially able to keep many separate clones of their slaves and occasionally pillage one or two for most of the essential genes. However, at some point in time, the number of captives reduced inside each gaoler to just one individual,” McFadden said.

“So if they broke into the alga’s cell to steal the last essential genes, they would destroy it in the process and would not then be able to use the genes to run photosynthesis. So the two cells, one captive and one captor, had apparently reached an evolutionary stand-off situation where both are dependent on each other to survive,” he said.

The article can be found at: Curtis BA et al. (2012) Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs.

Source: University of Melbourne

Samantha Chan | Featured Research

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International - Gene Variations Linked To Lung Cancer In Asian Women

An international group of scientists has identified three genetic regions that predispose Asian women who have never smoked to lung cancer.

An international group of scientists has identified three genetic regions that predispose Asian women who have never smoked to lung cancer.

The finding provides further evidence that risk of lung cancer among never-smokers, especially Asian women, may be associated with certain unique inherited genetic characteristics that distinguishes it from lung cancer in smokers.

The majority of lung cancers diagnosed historically among women in Eastern Asia have been in women who never smoked, and the specific genetic variations found in this study had not been associated with lung cancer risk in other populations.

Although environmental factors such as secondhand smoke (also known as environmental tobacco smoke) or exhaust from indoor cooking are likely account for some cases of lung cancer among never-smokers, they explain only a small proportion of the disease.

To gain a better understanding of lung cancer in Asian female never-smokers, researchers from the National Cancer Institute (NCI) in Bethesda, U.S. partnered with researchers from several countries in Asia (China, South Korea, Japan, Singapore) to create the Female Lung Cancer Consortium in Asia.

The consortium conducted one of the largest genome-wide association studies (GWAS) in female never-smokers to date. GWAS compares DNA markers across the genome between people with a disease or trait to people without the disease or trait.

“This study is the first large-scale genome-wide association study of lung cancer among never-smoking females anywhere in the world,” said study leader Dr. Qing Lan, a senior investigator in NCI’s Division of Cancer Epidemiology and Genetics.

The consortium, whose findings were reported online in the journal Nature Genetics, conducted a GWAS that combined data from 14 studies that included a total of approximately 14,000 Asian women (6,600 with lung cancer and 7,500 without lung cancer). The studies included data on environmental factors, including exposure to second-hand smoke.

The consortium found that variations at three locations in the genome — two on chromosome 6 and one on chromosome 10 — were associated with lung cancer in Asian female never-smokers. The discovery on chromosome 10 was particularly significant because it has not been found in any other GWAS of lung cancer in white or Asian populations.

“Our study provides strong evidence that common inherited genetic variants contribute to an increased risk of lung cancer among Asian women who have never smoked,” said senior investigator Dr. Nathaniel Rothman.

The researchers did not detect an association with variations at a location on chromosome 15 that has been associated with lung cancer risk in many previous GWAS of lung cancer in smokers. The absence of this association provides further support for the suggestion that the genetic variation on chromosome 15 may be smoking-related.

In addition, they found that Asian women with one of the newly identified genetic variants may be more susceptible to the effects of environmental tobacco smoke. However, more work is needed to draw definitive conclusions from this observation, they say.

The article can be found at: Lan Qin et al. (2012) Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

Source: NIH

Asian Scientist Newsroom | Health & Medicine

USA - Differences between human twins at birth highlight importance of intrauterine environment

Your genes determine much about you, but environment can have a strong influence on your genes even before birth, with consequences that can last a lifetime.

In a study published online in Genome Research, researchers have for the first time shown that the environment experienced in the womb defines the newborn epigenetic profile, the chemical modifications to DNA we are born with, that could have implications for disease risk later in life.

Epigenetic tagging of genes by a chemical modification called DNA methylation is known to affect gene activity, playing a role in normal development, aging, and also in diseases such as diabetes, heart disease, and cancer. Studies conducted in animals have shown that the environment shapes the epigenetic profile across the genome, called the epigenome, particularly in the womb. An understanding of how the intrauterine environment molds the human epigenome could provide critical information about disease risk to help manage health throughout life.

Twin pairs, both monozygotic (identical) and dizygotic (fraternal), are ideal for epigenetic study because they share the same mother but have their own umbilical cord and amniotic sac, and in the case of identical twins, also share the same genetic make-up. Previous studies have shown that methylation can vary significantly at a single gene across multiple tissues of identical twins, but it is important to know what the DNA methylation landscape looks like across the genome.

In this report, an international team of researchers has for the first time analyzed genome-scale DNA methylation profiles of umbilical cord tissue, cord blood, and placenta of newborn identical and fraternal twin pairs to estimate how genes, the shared environment that their mother provides and the potentially different intrauterine environments experienced by each twin contribute to the epigenome. The group found that even in identical twins, there are widespread differences in the epigenetic profile of twins at birth.

"This must be due to events that happened to one twin and not the other," said Dr. Jeffrey Craig of the Murdoch Childrens Research Institute (MCRI) in Australia and a senior author of the report. Craig added that although twins share a womb, the influence of specific tissues like the placenta and umbilical cord can be different for each fetus, and likely affects the epigenetic profile.

Interestingly, the team found that methylated genes closely associated with birth weight in their cohort are genes known to play roles in growth, metabolism, and cardiovascular disease, lending further support to a known link between low birth weight and risk for diseases such as diabetes and heart disease. The authors explained that their findings suggest the unique environmental experiences in the womb may have a more profound effect on epigenetic factors that influence health throughout life than previously thought.

Furthermore, an understanding of the epigenetic profile at birth could be a particularly powerful tool for managing future health. "This has potential to identify and track disease risk early in life, said Dr. Richard Saffery of the MCRI and a co-senior author of the study, "or even to modify risk through specific environmental or dietary interventions."

More information: Gordon L, Joo JE, Powell JE, Ollikainen M, Novakovic B, Li X, Andronikos R, Cruickshank MN, Conneely KN, Smith AK, Alisch RS, Morley R, Visscher PM, Craig JM, Saffery R. Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence. Genome Res doi: 10.1101/gr.136598.111

Journal reference: Genome Research   

Provided by Cold Spring Harbor Laboratory

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Singapore - Medical genetics: Gene markers of kidney disease

Variations in immune genes associated with increased susceptibility to common kidney disease

IgA nephropathy (IgAN) is the most common condition affecting the glomeruli, or small blood vessels in the kidney. It is characterised primarily by the deposition of IgA antibodies in the glomeruli, which leads to inflammation and scarring of the blood vessels. The disease is more prevalent in Asian than in Western countries, and although genetic and environmental factors play a role in its development, very little is known about the genetic risk factors involved.

A large team of researchers led by Jianjun Liu at the A*STAR Genome Institute of Singapore have identified a number of genetic variants that are associated with increased risk of a common kidney disease called IgAN in Chinese individuals of Han descent1.

Liu and his co-workers performed a genome-wide association study comparing the genomic data of nearly 1,500 Han Chinese individuals with IgAN with those of approximately 2,700 healthy controls. In the first phase of the study, they analysed almost 450,000 common single nucleotide polymorphisms (SNPs), or sequence variations at individual positions in the DNA sequence. This confirmed that a number of known genetics variants are associated with increased susceptibility to IgAN.

The researchers also identified several more previously unknown genetic variants. After confirming these initial findings, they analysed these genetic variants in another 2,700 individuals with IgAN and about 3,500 controls.

Some of the newly identified SNPs lie within the region of the genome containing the major histocompatibility complex (MHC) genes, which encode proteins that are critical for proper function of the immune system. Other SNPs were found in the genes encoding tumour necrosis factor, a signalling molecule that is important for the development of B cells of the immune system, and α-defensins, a group of molecules that have antibiotic properties and are involved in the inflammatory response to infection. They also provide migratory cues for immune cells and induce them to release small signalling molecules called cytokines.

The findings show that variations in genes involved in immunity and inflammation can influence susceptibility to IgAN and the development of the disease.

“These novel SNPs have not been studied in non-Chinese population yet, so we don't

know whether they will show the similar association in other populations,” says Liu. “The SNPs only explain a small proportion of genetic risk for IgAN and many additional genetic risk variants need to be discovered. We are collaborating with other groups on a meta-analysis of IgAN where independent GWAS datasets will be combined to discover new variants.”

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore

References

1. Yu, X.-Q. et al. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nature Genetics 44, 178–182 (2012). | article

Australia - Genes Associated With Childhood Obesity Identified In Largest Ever Study

A large international collaborative study has identified at least two new gene variants that increase the risk of common childhood obesity.

An international collaborative study conducted by the Early Growth Genetics (EGG) Consortium has identified at least two new gene variants that increase the risk of common childhood obesity.

The study, to date the largest ever genome-wide analysis of common childhood obesity, involved 5,530 cases of childhood obesity and 8,300 control subjects of normal weight, all of European ancestry.

In the latest online issue of Nature Genetics, the researchers identified two novel loci associated with common childhood obesity, one near the OLFM4 gene on chromosome 13 and the other within the HOXB5 gene on chromosome 17.

Two other gene variants were also found to be linked to obesity, and none of the four gene loci were previously implicated in common childhood obesity.

“Previous studies have focused on more extreme forms of obesity primarily connected with rare disease syndromes, while this study includes a broader range of children,” said Associate Professor Craig Pennell of the University of Western Australia. “We have identified and characterized two new genetic variants that are associated with a predisposition to common childhood obesity.”

Established research indicates that obese adolescents tend to have a higher risk of mortality when they are adults. Although environmental factors, such as food choices and sedentary habits, contribute to the increasing rates of obesity in childhood, twin studies and other family-based evidence have suggested a genetic component as well.

While previous studies have identified gene variants contributing to obesity in adults and in children with extreme obesity, relatively little is known about genes implicated in regular childhood obesity.

“This work opens up new avenues to explore the genetics of childhood obesity,” Pennell said. “A great deal of work remains, however, these findings may ultimately be useful in helping to design preventive interventions and treatments for children, based on their individual genomes.”

The article can be found at: Bradfield (2012) A Genome-Wide Association Meta-Analysis Identifies New Childhood Obesity Loci.

Source: University of Western Australia.

Anusuya Das | Health & Medicine

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Sweden - Exercise gives genes a workout, but can coffee do the same?

The relationship between mocha-lattes and pilates might be deeper than you think. Credit: Brian Wilkins

Have you ever wondered how you could get more out of your workouts? And have you ever wondered what actually happens to your muscles when you exercise?

Recent studies have begun to look, in detail, at the changes that occur in the way our genes are used both during and after exercise. And the results of the most recent study, by Dr. Juleen Zierath and colleagues, might hold insights into why our fitness trails off after stopping exercise.

But first, a bit of background

Of the tens of thousands of genes you have in each and every cell of your body, only a subset are used at any one time in each cell. If a gene is used, the information within is used to create a protein product; a process called gene expression.

The genes that are used (the gene expression, in other words) then determines the function of the cell in question. A different set of genes being expressed will produce a cell that fulfils a different purpose.

For instance, red blood cells express the haemoglobin gene and so make haemoglobin, which can bind oxygen, and allows these cells to traffic oxygen around the body. Other blood cells that fight infection, the white blood cells, produce toxic chemicals and enzymes to attack the invading infection.

Over the last few years, it has been shown that exercise rapidly induces changes in gene expression in the skeletal muscle cells.

These are cells that you voluntarily contract when you exercise – such as your thigh muscles – rather than say the heart muscle, which contracts without you thinking about it, even when you’re asleep.

Most of the changes in genes induced by exercise are related to the usage of energy within the skeletal muscle cell. Interestingly, these changes are proportional to how hard you train: higher intensity exercise leads to more dramatic changes in the skeletal muscle cells.

This makes sense: the harder you train, the more energy is required by your muscles. The changes in the energy-usage genes are also maintained long after you’ve finished your workout.

This helps to explain why your metabolic rate – the amount of energy you burn – is high during the workout and for several hours afterwards.

So how does a skeletal muscle cell bring about the quick changes in the genes that are used, to rapidly provide the energy required for exercise? And how do they allow the energy-usage genes to be switched on?

Well, we know calcium is released within the cell, sending a signal to alter gene expression. But then how does the calcium signal alter which genes are expressed?

X

The recent study by Dr. Zierath and colleagues, published in the Cell Metabolism journal, has started to address this question.

They looked at small modifications made to the genes in skeletal muscle cells, called epigenetic marks.

Epigenetic marks are tags associated with your genes that help a cell interpret when to use a gene and when to switch a gene off.

One way to think of epigenetic marks is as the punctuation marks in the cell. Punctuation marks don’t change the words themselves, they just help us to read a sentence. The same is true of epigenetic marks: they don’t change the genetic information, they just help the cell to make sense of that genetic information.

Dr. Zierath’s group found that exercise induces skeletal muscle cells to switch on the energy-usage genes while removing some epigenetic marks from the energy-usage genes.

Like the changes in the gene expression itself, these changes in epigenetic marks are rapidly induced and are maintained for several hours after the exercise session.

But the epigenetic changes are not retained for even a couple of days after a three-week training program – the length of time the study’s subjects were asked to train for.

Most athletes know that peak fitness is only retained for a day or so after completing a training program. Could the work of Zierath and colleagues explain why?

That is, does fitness wear off because the epigenetic marks on energy-usage genes within skeletal muscle cells have returned to normal?

X

Perhaps even more interesting is a small part of Dr. Zierath’s study which showed that some of the changes in gene expression and epigenetic marks on energy-usage genes can be mimicked by caffeine.

Your daily coffee could be giving your genes a workout!

It’s been known for some time that many of the gene expression changes induced by exercise can also be influenced by signals from the brain or hormones in your blood stream. But in the case of caffeine, we are clearly much more able to manipulate the system to our advantage.

There is still much to be learnt about caffeine-induced changes in gene expression, and how it compares to actually working up a sweat at the gym.

Many intriguing questions remain, not least of which: does caffeine exposure alter the effectiveness of your training?

No-one would recommend a coffee rather than exercise but maybe a coffee before your workout could actually enhance your body’s physiological response to exercise … even if the coffee does leave you dehydrated and jittery.

This is certainly something worth testing. On the flip side, these effects may add weight to recent calls for caffeine bans to be reintroduced to competitive sports.

Source: The Conversation (news : web)

This story is published courtesy of the The Conversation (under Creative Commons-Attribution/No derivatives).

Marnie Blewitt

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Australia - Researchers discover genes for fracture susceptibility and osteoporosis risk

The University of Queensland Diamantina Institute's researchers have played a leading role in a recent study into osteoporosis, more than doubling the number of currently known genes in the disease.

Osteoporosis is a silent but frequent and devastating age-related disease: in Australia 25 per cent of women wtih hip fracture die within 12 months, with an even higher mortality rate for men with hip fracture.

Women older than 65 years are at greater risk for death after hip fracture than from breast cancer.

While the consequences of osteoporosis are well established, the causes of the disease remain elusive.

It has been known for a long time that osteoporosis is strongly genetically determined, but the responsible genes had remained largely unknown.

This situation has changed dramatically, due to the recent discoveries of UQDI researchers and their collaborators.

In their study published in the leading genetic journal Nature Genetics, variants in 56 regions of the genome have been discovered to influence the Bone Mineral Density (BMD) of individuals.

Fourteen of these variants were also found to increase the risk of fracture.

This single study doubles the number of known genes for BMD, and is the first time such large number of genetic variants have been found to be associated with fracture risk.

Bone mineral density measured by Dual Energy X-Ray absorptiometry (DXA) is the most widely used measurement to diagnose osteoporosis and to assess the risk of fracture.

In general terms high BMD results in lower risk of fracture.

UQDI researchers Associate Professor Emma Duncan and Professor Matt Brown played leading roles in the international consortium of investigators from across Europe, North America, East Asia and Australia, bringing together more than 50 independent studies.

Overall, the study involved more than 80,000 individuals with DXA scans to assess BMD; and more than 30,000 cases with fracture and 100,000 controls without fracture were studied in what constitutes the largest genetic study in osteoporosis performed to date.

“The Australian Osteoporosis Genetics Consortium played a key role in this recent paper,” Associate Professor Duncan said.

“Our own study, involving bone researchers from Australia, New Zealand and the United Kingdom, and supported by the National Health and Medical Research Council of Australia, was particularly important because of our unique approach of recruiting individuals with more extreme bone density.

"This meant that although we contributed a modest number of individuals to this current study, their impact was disproportionately powerful; and as a consequence the Australian contribution was the most powerful individual component of the entire project overall."

Further, work by UQ's Dr Dana Willner during her time at UQDI was responsible for identifying critical molecular pathways that are now candidates for therapeutic applications.

Dr Fernando Rivadeneira, who is an Assistant Professor at the Erasmus Medical Centre in Rotterdam, Netherlands, and lead senior author of the study said: “Such potential is highlighted by the identification (among others) of genes encoding proteins that are currently subject to novel bone medications.

"Yet, even more interesting is the identification of several factors that can constitute targets for true bone-building drugs.”

This research leads to greater understanding of the biology of skeletal health and fracture susceptibility.

“In addition to the known proteins and pathways we have identified we are also confronted with completely new biology,” said Karol Estrada, scientific researcher at Erasmus MC and first author of the publication.

“There is, for example, very little known about the genomic region on chromosome 18 where we discovered the strongest genetic factor associated with fracture risk.

"Just less than a month ago the factor underlying the genetic signal was recognised as a gene, now known as FAM210A."

Dr Douglas Kiel is Professor of Medicine at Harvard Medical School and the Institute for Aging Research at Hebrew SeniorLife in Boston, MA in the USA and senior author co-leading the study.

“We also established that, as compared to women carrying the normal range of genetic factors, women with an excess of BMD-decreasing genetic variants had up to 56 per cent higher risk of having osteoporosis and 60 per cent increased risk for all-types of fractures,” he said.

“Even more interesting is our discovery of groups of individuals with a smaller number of variants which protected them against developing osteoporosis or sustaining fractures."

André Uitterlinden, Professor of Complex Genetics at Erasmus MC said the genome-wide association approach would mean researchers could continue to identify hundreds of common variants underlying the risk of osteoporosis and fracture.

“Nevertheless, we will need new technologies and approaches to understand more,” he said.

Professor Matthew Brown agrees.

“Researchers at UQDI have been doing exactly this, by performing a whole-exome sequencing project in 1000 individuals from our Australian Osteopororis Genetics Consortium," he said.

"This further study, also supported by the NHMRC, will help us to understand the genetic underpinnings of this complex disease that is osteoporosis."

Provided by University of Queensland (news : web)

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USA - Genes that promote cartilage healing protect against arthritis

In mice with ears that heal rapidly, cartilage (shown in the thick blue border) also regenerates and heals more quickly. Washington University researchers found that the same genes that promote healing after cartilage damage also appear to protect against osteoarthritis. (SANDELL LABORATORY)

The same genes that promote healing after cartilage damage also appear to protect against osteoarthritis, a condition caused by years of wear-and-tear on the cartilage between joints, new research at Washington University School of Medicine in St. Louis shows.

Although the research was conducted in mice, the genes also are likely to be important in people.

“Our goal is to see whether we can protect cartilage in people by detecting the early biological changes that occur in osteoarthritis and prevent it from progressing to the stage where joint replacement becomes necessary,” says principal investigator Linda J. Sandell, PhD, the Mildred B. Simon Professor of Orthopaedic Surgery. “The main problem with biological treatments is that currently, we can’t detect osteoarthritis in its early stages. Better understanding of the genes that influence the disorder may help us do that.”

The researchers reported their findings in a pair of studies, published online in the journals Arthritis & Rheumatism and Osteoarthritis and Cartilage.

Osteoarthritis is the most common form of arthritis, affecting 25 million people in the United States. It is linked to the breakdown of cartilage, which acts as a shock absorber to cushion the joints. Osteoarthritis causes pain, swelling and reduced motion and is most common in the hands, knees, hips or spine.

Scientists first discovered cartilage-healing properties in some strains of laboratory mice when they pierced their ears as a means to tag and identify them. But in some mice, the holes in their ears closed and quickly healed. Because so much of the ear is made from cartilage and healing occurred so rapidly in the mice ears, the researchers suspected that these mice also may be able to regenerate cartilage in their joints.

Sandell and her team bred the mice that healed rapidly with other mice that healed more slowly, and they found that the mice that could quickly heal and regenerate cartilage in the knee also were less susceptible to osteoarthritis.

In people, a breakdown of cartilage causes the bones to rub together and damage the joint. If the damage becomes too extensive, joint replacement surgery may be necessary.

Injury to a joint is a major risk factor for osteoarthritis, but not everyone is equally susceptible.

“Some people – and these mouse studies suggest that someday we may be able to predict which people – fare much better after an injury,” Sandell says. “We want to find a way to identify the genes that protect them.”

Sandell, director of the university’s Core Center for Musculoskeletal Biology and Medicine, and co-investigator James M. Cheverud, PhD, professor of anatomy and neurobiology, now are studying several other strains of mice on the spectrum between the good healers and those that heal poorly. They’ve looked at the cartilage tissue under the microscope to determine the extent of osteoarthritis following an injury and analyzed the DNA in cartilage.

“We’ve identified genes that correlate with healing and with protection from osteoarthritis,” Sandell says. “The work is in its beginning stages, but now that we’ve found a correlation, we want to look at even more strains of mice so that we can actually map the location of the genes that cause osteoarthritis and help to repair cartilage.”

She says osteoarthritis, like several other disorders, will ultimately involve many genes that each contribute in a small way to the disease process. By looking at more strains of mice, the research team believes it will become easier to identify the subtle genetic influences on osteoarthritis risk. As they clarify which genes are protecting the mice, it will be possible to look for similar genes in humans.

More information: Rai MF, Hashimoto S, Johnson EE, Janiszak KL, Fitzgerald J, Heber-Katz E, Cheverud JM, Sandell LJ. Heritability of articular cartilage regeneration and its association with ear-wound healing. Arthritis & Rheumatism, vol. 64 (published online). DOI 10.1002/art.34396

Hashimoto S, Rai MF, Janiszak KL, Cheverud JM, Sandell LJ. Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice. Osteoarthritis and Cartilage, vol. 20 (published online). doi: 10.1016/j.joca.2012.01.022

Provided by Washington University School of Medicine in St. Louis (news :web)

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USA - Structure of a Key 'Gene Silencer' Protein Discovered: Potential Therapeutic Targets With 'Untapped Potential'

Scientists at The Scripps Research Institute have determined the three-dimensional atomic structure of a human protein that is centrally involved in regulating the activities of cells. Knowing the precise structure of this protein paves the way for scientists to understand a process known as RNA-silencing and to harness it to treat diseases.

"Biologists have known about RNA-silencing for only a decade or so, but it's already clear that there's an enormous untapped potential here for new therapies," said Ian MacRae, an assistant professor at Scripps Research and senior author of the new report.

The new report, which appeared on April 26, 2012 in the journal Science's advance online publication, Science Express, focuses on Argonaute2. This protein can effectively "silence" a gene by intercepting and slicing the gene's RNA transcripts before they are translated into working proteins.

Interception and Destruction of Messages

When a gene that codes for a protein is active in a cell, its information is transcribed from DNA form into lengths of nucleic acid called messenger RNA (mRNA). If all goes well, these coded mRNA signals make their way to the cell's protein-factories, which use them as templates to synthesize new proteins. RNA-silencing, also called RNA interference (RNAi), is the interception and destruction of these messages -- and as such, is a powerful and specific regulator of cell activity, as well as a strong defender against viral genes.

The silencing process requires not only an Argonaute protein but also a small length of guide RNA, known as a short-interfering RNA or microRNA. The guide RNA fits into a slot on Argonaute and serves as a target recognition device. Like a coded strip of VelcroTM, it latches onto a specific mRNA target whose sequence is the chemical mirror image, or "complement," of its own -- thus bringing Argonaute into contact with its doomed prey.

Argonaute2 is not the only type of human Argonaute protein, but it seems to be the only one capable of destroying target RNA directly. "If the guide RNA is completely complementary to the target RNA, Argonaute2 will cleave the mRNA, and that will elicit the degradation of the fragments and the loss of the genetic message," said Nicole Schirle, the graduate student in MacRae's laboratory who was lead author of the paper.

Aimed at disease-causing genes or even a cell's own overactive guide RNAs, RNA-silencing could be a powerful therapeutic weapon. In principle, one needs only to inject target-specific guide RNAs, and these will link up with Argonaute proteins in cells to find and destroy the target RNAs. Scientists have managed to do this successfully with relatively accessible target cells, such as in the eye. But they have found it difficult to develop guide RNAs that can get from the bloodstream into distant tissues and still function.

"You have to modify the guide RNA, in some way to get it through the blood and into cells, but as soon as you start modifying it, you disrupt its ability to interact with Argonaute," said MacRae. Knowing the precise structure of Argonaute should enable researchers to clear this hurdle by designing better guide RNA.

More Points for Manipulation

Previous structural studies have focused mostly on Argonaute proteins from bacteria and other lower organisms, which have key differences from their human counterparts. Schirle was able to produce the comparatively large and complex human Argonaute2 and to manipulate it into forming crystals for X-ray crystallography analysis -- a feat that structural biologists have wanted to achieve for much of the past decade. "It was just excellent and diligent crystallography on her part," said MacRae.

The team's analysis of Argonaute2's structure revealed that it has the same basic set of working parts as bacterial Argonaute proteins, except that they are arranged somewhat differently. Also, key parts of Argonaute2 have extra loops and other structures, not seen on bacterial versions, which may play roles in binding to guide RNA. Finally, Argonaute2 has what appear to be binding sites for additional co-factor proteins that are thought to perform other destructive operations on the target mRNA.

"Basically, this Argonaute protein is more sophisticated than its bacterial cousins; it has more bells and whistles, which give us more points for manipulation. With this structure solved, we no longer need to use the prokaryotic structures to guess at what human Argonaute proteins look like," MacRae said.

He and Schirle and others in the lab now are analyzing the functions of Argonaute2's substructures, as well as looking for ways to design better therapeutic guide RNAs.

"Now with the structural data, we can see what synthetic guide RNAs will work with Argonaute and what won't," MacRae said. "We might even be able to make guide RNAs that can outcompete natural ones."

The research was funded by the National Institute of General Medical Sciences, part of the National Institutes of Health.

ScienceDaily

UK - Key genes that switch off with aging highlighted as potential targets for anti-aging therapies

Researchers at King's College London, in collaboration with the Wellcome Trust Sanger Institute, have identified a group of 'ageing' genes that are switched on and off by natural mechanisms called epigenetic factors, influencing the rate of healthy ageing and potential longevity.

The study also suggests these epigenetic processes – that can be caused by external factors such as diet, lifestyle and environment – are likely to be initiated from an early age and continue through a person's life. The researchers say that the epigenetic changes they have identified could be used as potential 'markers' of biological ageing and in the future could be possible targets for anti-ageing therapies.

Published today in PLoS Genetics, the study looked at 172 twins aged 32 to 80 from the TwinsUK cohort based at King's College London and St Thomas' Hospital, as part of King's Health Partners Academic Health Sciences Centre.

The researchers looked for epigenetic changes in the twins' DNA, and performed epigenome-wide association scans to analyse these changes in relation to chronological age. They identified 490 age related epigenetic changes. They also analysed DNA modifications in age related traits and found that epigenetic changes in four genes relate to cholesterol, lung function and maternal longevity.

To try to identify when these epigenetic changes may be triggered, the researchers replicated the study in 44 younger twins, aged 22 to 61, and found that many of the 490 age related epigenetic changes were also present in this younger group. The researchers say these results suggest that while many age related epigenetic changes happen naturally with age throughout a person's life, a proportion of these changes may be initiated early in life.

Dr Jordana Bell from King's College London, who co-led the study said: 'We found that epigenetic changes associate with age related traits that have previously been used to define biological age.

'We identified many age-related epigenetic changes, but four seemed to impact the rate of healthy ageing and potential longevity and we can use these findings as potential markers of ageing. These results can help understand the biological mechanisms underlying healthy ageing and age-related disease, and future work will explore how environmental effects can affect these epigenetic changes.'

Dr Panos Deloukas, co-leader of the study from the Wellcome Trust Sanger Institute, said: 'Our study interrogated only a fraction of sites in the genome that carry such epigenetic changes; these initial findings support the need for a more comprehensive scan of epigenetic variation.'

Professor Tim Spector, senior author from King's College London, said: 'This study is the first glimpse of the potential that large twin studies have to find the key genes involved in ageing, how they can be modified by lifestyle and start to develop anti-ageing therapies. The future will be very exciting for age research.'

Provided by King's College London (news : web)

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UK - Scientists find new breast cancer genes, rewrite rulebook

Scientists at the BC Cancer Agency and University of British Columbia have identified new breast cancer genes that could change the way the disease is diagnosed and form the basis of next-generation treatments.

Researchers have reclassified the disease into 10 completely new categories based on the genetic fingerprint of a tumour. Many of these genescould offer much-needed insight into breast cancer biology, allowing doctors to predict whether a tumour will respond to a particular treatment. Whether the tumour is likely to spread to other parts of the body or if it is likely to return following treatment.

The study, published online today in the international journal Nature, is the largest global study of breast cancer tissue ever performed and the culmination of decades of research into the disease.

In the future, this information could be used by doctors to better tailor treatment to the individual patient.

"This is a major step forward in building the genetic encyclopedia of breast cancer and in the process we've learned there are many more subtypes of breast cancer than we imagined. The new molecular map of breast cancer points us to new drug targets for treating breast cancer and also defines the groups of patients who would benefit most." said Dr. Sam Aparicio, study co-lead author. "The size of this study is unprecedented and provides insights into the disease such as the role of immune response, which will stimulate other avenues of research.

The team at the BC Cancer Agency, in collaboration with Cancer Research UK's Cambridge Research Institute and Manitoba Institute of Cell Biology at University of Manitoba, analyzed the DNA and RNA of 2,000 tumour samples taken from women diagnosed with breast cancer between five and 10 years ago. The sheer number of tumours mapped allowed researchers to spot new patterns in the data.

Study milestones include:

·         Classified breast cancer into 10 subtypes grouped by common genetic features, which correlate with survival. This new classification could change the way drugs are tailored to treat women with breast cancer.

·         Discovered several completely new genes that had never before been linked to breast cancer. These genes that drive the disease are all targets for new drugs that may be developed. This information will be available to scientists worldwide to boost drug discovery and development.

·         Revealed the relationship between these genes and known cell signaling pathways – networks that control cell growth and division. This could pinpoint how these gene faults cause cancer, by disrupting important cell processes.

This is the second major breakthrough announced by BC Cancer Agency scientists in as many weeks. On April 4, a team led by Dr. Sam Aparicio celebrated the decoding of the genetic makeup of the most-deadly of breast cancers, triple-negative breast cancer, which until then was defined by what it was missing, not what it was. Similar to that announcement, today's new discovery identifies genes that were previously unknown to be linked to breast cancer and makes it clear that breast cancer is an umbrella term for what really is a number of unique diseases.

While the research is unlikely to benefit women who currently have breast cancer, it substantially advances how scientists approach further research and clinical trials by providing them with a springboard to develop new treatment options and drugs targeted to specific genes.

More information: "The integrative genomic and transcriptomic architecture of 2000 breast tumours." Curtis et al. Nature. DOI: 10.1038/nature10983

Provided by University of British Columbia (news : web)

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