A new study provides insight on the potential role played by RNA (ribonucleic acid) editing in cancer.

The findings may further our understanding of an emerging mechanism implicated in tumour initiation and progression, and may thus lead to the development of better treatment options in the future.

In every healthy human cell, the genetic information hard-wired into the DNA is transcribed into messenger RNA, which is in turn translated into proteins, the workhorses of all body tissues and organs. The prevailing view is that most malignancies are caused by DNA mutations, which can lead to the aberrant activation or inactivation of the corresponding protein products and to the consequent out-of-control growth and proliferation of malignant cells. RNA editing, the process by which ‘mutations’ of the RNA sequence are introduced post-transcriptionally, has the potential to impact a variety of cellular processes yet the precise mechanism of how has been poorly understood until now.

Previous studies have shown that more than one million sites in the genome are edited to various degrees. Despite the fact that a majority of these editing sites fall within regions that are not translated to protein, it has been shown that the differences in RNA editing levels between tumour and normal tissues are associated with different clinical outcomes. Currently, only a few coding RNA editing sites have been functionally characterized. However, it is still a puzzle whether and how the majority of the RNA editing events in the un-translated regions affect tumour growth.

Researchers from Boston University School of Medicine (BUSM) analysed 14 tumour types, and identified more than 2,000 genes showing significant changes in RNA editing level between tumour and normal tissues.

“This study suggests that RNA editing may serve as an important epigenetic mechanism of cellular regulation beyond the genetic/DNA level,” explained corresponding author Stefano Monti, PhD, associate professor of medicine at BUSM. “We show that the effect of one epigenetic component can be offset by changes in another epigenetic component. Thus, it is important to have a comprehensive picture of changes in the cancer genome, which may point to vulnerabilities amenable to targeted treatment,” added lead author Liye Zhang, PhD, postdoctoral fellow at BUSM. Boston University School of Medicine

Researchers funded by the National Institutes of Health have discovered the cellular switch that boosts the activity of sperm cells so that they can travel to the egg.  The finding may lead to new options for male contraception as well as treatments for infertility resulting from problems with sperm mobility.

Inside the male reproductive tract, mature sperm are capable of limited movement. This limited movement, however, is not enough to propel them toward the egg when they enter the female reproductive tract. To begin their journey, they must first be activated by the hormone progesterone, which is released by the egg.

The researchers report that the molecule to which progesterone must bind is the enzyme alpha/beta hydrolase domain containing protein 2 (ABHD2), found in the sperm cell’s outer membrane. The study was conducted by Melissa R. Miller and colleagues at the University of California, Berkley, the University of California, San Francisco, and Yale University School of Medicine in New Haven, Connecticut.

“This is an important advance in explaining how sperm become hypermotile in the female reproductive tract,” said Stuart Moss, Ph.D, director of the male reproductive health program at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, which funded the study.

“Developing new compounds that block ABHD2 ultimately may yield new contraceptive methods to prevent sperm from reaching the egg.”

Similarly, strategies to bypass or enhance the enzyme might provide therapies for treating infertility resulting from sperm that lack movement capability.

Before a sperm can transition to the hyper-active phase, calcium must pass through the cell’s outer membrane and enter the flagella, the tail-like appendage the cell uses to propel itself.  The sperm protein known as CatSper joins with similar proteins in the flagella to allow the entry of calcium.

When the researchers undertook the current study, it was not known whether progesterone interacted directly with CatSper to trigger the calcium influx, or acted on some other molecule (which, in turn, acted on CatSper). Before treating sperm with progesterone, the researchers exposed them to a chemical that inhibits a particular class of enzymes that they believed could include the candidate molecule that acted on CatSper. The hunch proved correct: the treated cells remained inactive after progesterone exposure, indicating that CatSper was not directly involved.

Working with modified progesterone, the researchers eventually isolated ABHD2 from the sperm tails. When the researchers inactivated ABHD2, exposure to progesterone failed to activate the sperm cells, confirming that ABHD2 is the molecular target for progesterone. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

New light has been shed on the genetic relationship between autistic spectrum disorders (ASD) and ASD-related traits in the wider population, by a team of international researchers including academics from the University of Bristol, the Broad Institute of Harvard and MIT, and Massachusetts General Hospital (MGH).

The researchers studied whether there is a genetic relationship between ASD and the expression of ASD-related traits in populations not considered to have ASD. Their findings suggest that genetic risk underlying ASD, including both inherited variants and de novo influences (not seen in an individual’s parents), affects a range of behavioural and developmental traits across the population, with those diagnosed with ASD representing a severe presentation of those traits.

Autism spectrum disorders (ASD) are a class of neurodevelopmental conditions affecting about 1 in 100 children. They are characterised by social interaction difficulties, communication and language impairments, as well as stereotyped and repetitive behaviour. These core symptoms are central to the definition of an ASD diagnosis but also occur, to varying degrees, in unaffected individuals and form an underlying behavioural continuum.

With recent advances in genome sequencing and analysis, a picture of ASD’s genetic landscape has started to take shape. Research has shown that most ASD risk is polygenic (stemming from the combined small effects of thousands of genetic differences, distributed across the genome). Some cases are also associated with rare genetic variants of large effect, which are usually de novo.

 “There has been a lot of strong but indirect evidence that has suggested these findings,” said Dr Mark Daly, co-director of the Broad Institute’s Medical and Population Genetics (MPG) Program and senior author of the study.

“Once we had measurable genetic signals in hand – both polygenic risk and specific de novo mutations known to contribute to ASD – we were able to make an incontrovertible case that the genetic risk contributing to autism is genetic risk that exists in all of us, and influences our behaviour and social communication.”

Study co-first author Dr Elise Robinson, from MGH, said: “We can use behavioural and cognitive data in the general population to untangle the mechanisms through which different types of genetic risk are operating. We now have a better path forward in terms of expecting what types of disorders and traits are going to be associated with certain types of genetic risk.”

“Our study shows that collecting and using phenotypic and genetic data in typically developing children can be useful in terms of the design and interpretation of studies targeting complex neurodevelopmental and psychiatric disorders,’ said study co-first author Dr Beate St Pourcain, from the Medical Research Council Integrative Epidemiology Unit at the University of Bristol and the Max Planck Institute for Psycholinguistics.

“Based on the genetic link between population-based social-communication difficulties and clinical ASD, we may now gain further phenotypic insight into a defined set of genetically-influenced ASD symptoms. This may help us to identify and investigate biological processes in typically-developing children, which are disturbed in children with ASD.” University of Bristol

Researchers at the University of Southampton have discovered specific markers on DNA that link the season of birth to risk of allergy in later life.
The season a person is born in influences a wide range of things: from risk of allergic disease, to height and lifespan. Yet little is known about how a one-time exposure like the season of birth has such lasting effects.

The Southampton study conducted epigenetic scanning on DNA samples from a group of people born on the Isle of Wight. They found that particular epigenetic marks (specifically, DNA methylation) were associated with season of birth and still present 18 years later. The research team was also able to link these birth season epigenetic marks to allergic disease, for example people born in autumn had an increased risk of eczema compared to those born in spring. The results were validated in a cohort of Dutch children.

John Holloway, Professor of Allergy and Respiratory Genetics at the University and one of the study’s authors, comments: “These are really interesting results. We know that season of birth has an effect on people throughout their lives. For example generally, people born in autumn and winter are at increased risk for allergic diseases such as asthma. However, until now, we did not know how the effects can be so long lasting.

“Epigenetic marks are attached onto DNA, and can influence gene expression (the process by which specific genes are activated to produce a required protein) for years, maybe even into the next generation. Our study has linked specific epigenetic marks with season of birth and risk of allergy. However, while these results have clinical implications in mediating against allergy risk, we are not advising altering pregnancy timing.”

Dr Gabrielle Lockett, of the University of Southampton and first author of the study, adds: “It might sound like a horoscope by the seasons, but now we have scientific evidence for how that horoscope could work. Because season of birth influences so many things, the epigenetic marks discovered in this study could also potentially be the mechanism for other seasonally influenced diseases and traits too, not just allergy.”

The team say that further research is needed to understand what it is about the different seasons of the year that leads to altered disease risk, and whether specific differences in the seasons including temperature, sunlight levels and diets play a part. More study is also needed on the relationship between DNA methylation and allergic disease, and whether other environmental exposures also alter the epigenome, with potential disease implications. University of Southampton

At age 56, Roma Jean Ockler was continually afflicted with sinus infections and pneumonia, and despite treatments, only seemed to be getting worse. For decades, immunologist Harry R. Hill, M.D., had seen patients like her. At the time he couldn’t have known that her family’s genetic information, combined with that of five other families from across the world, would classify a new disorder. Their subtype of common variable immunodeficiency disorder (CVID) results from mutations in IKAROS, a protein well known for its central role in immune cell development. The new findings make possible a definitive genetic diagnosis for this class of CVID, opening a door to precision medicine tailored to patients with the disorder.

The research was a collaboration between Hill and his colleagues Attila Kumánovics, M.D., Karl Voelkerding, M.D., Sarah South, Ph.D., Nancy Augustine, and Thomas Martins, M.S., from the University of Utah School of Medicine and the ARUP Institute for Clinical and Experimental Pathology at ARUP Laboratories in Salt Lake City, and 26 other scientists from institutions across the U.S. and Europe.

One of the most frustrating aspects of CVID is that it’s difficult to diagnose early before serious complications develop, says Hill. Occurring in about 1 in 20,000 people, the rare condition is actually a collection of disorders that cause a susceptibility to infection, as seen in Ockler’s case. Her illnesses worsened considerably over time but because doctors did not diagnose her, she was not given appropriate treatment. By the time she saw Hill for the first time, she had been through 17 years of sinus surgeries, pneumonias, and a life-threatening intestinal infection. Based on experience he prescribed an immunoglobulin regimen that has since quieted her symptoms.

The genetic causes of only about 15 percent of CVID cases have been identified, and Ockler did not have any of them. When Hill learned she had relatives with similar symptoms, he saw an opportunity to define her condition.

“We knew that if we could find the cause of her and her extended family’s disorder that we would have the chance to keep others from going through what she had,” says Hill, professor of pathology, paediatrics and medicine.

In collaboration with molecular pathologists Kumánovics and Voelkerding, they found that many of her relatives were missing one of two copies of a gene that codes for IKAROS. Meanwhile, Mary Ellen Conley, M.D., from The Rockefeller University, independently came to the same conclusion with her own patients. She connected with the Utah team and coordinated what would become an international effort revealing a total of six unrelated families who share similar sets of symptoms, and changes in the same gene, implicating IKAROS as the culprit behind their shared disorder. “Often research tries to answer a question that is brought up by the patients,” says Conley.      

Harry HillWhile some families had a change in just one DNA letter within the gene, others were missing a large piece, or all of it. Each of the mutations cripple a region required for IKAROS to function, a result confirmed by biochemical analysis, suggesting it cannot carry out its critical role in regulating immune B cell development. Indeed, as the experiments predicted, all six families have low B cell counts. In other words, their immune system is misconstructed, likely explaining why they also have low levels of infection-fighting antibodies (immunoglobulins).

Yet one of the most surprising findings, says Kumánovics, assistant professor of pathology, is that while some who carry the IKAROS mutations are prone to sickness, others appear to be healthy. He adds that understanding the biology that leads to this unexpected resilience could provide clues to overcoming the condition. “These rare patients don’t know how valuable they are. They are providing insights into how the immune system works,” he says. University of Utah