Researchers at the Babraham Institute have revealed a new understanding of the molecular switches that control gene activity in human embryonic stem cells.
In the developing embryo and during the specialisation of stem cells, the activity of genes must be tightly controlled so that the correct genes are switched on and off at the right time and in the right cells. One of the main ways that this process is regulated is by a protein complex called Polycomb Repressive Complex 2 (PRC2), which keeps genes switched off until they are needed. Earlier research showed that PRC2 is necessary for controlling gene activity during the development of the fruit fly and the mouse. Current research study focusses PRC2’s role in human embryonic stem cells.
As described in the journal Cell Reports, the researchers used the CRISPR gene editing technique to delete PRC2 from human embryonic stem cells. Loss of PRC2 caused the cells to switch on many genes that are not normally active in these cells.These changes led to the inability of embryonic stem cells lacking PRC2 to specialize correctly into mature cell types.
Dr Peter Rugg-Gunn, senior author on the research paper and research group leader at the Babraham Institute explained: “This work is exciting because it reveals that gene activity is controlled by similar molecular switches in human development as in other species such as the fly and mouse. We have also uncovered human-specific differences in the way that embryonic stem cells respond to genes being misregulated. These findings provide new insights into the development of our own species, and might enable new ways to turn embryonic stem cells into useful cell types, such as heart and pancreas, which can be used for cell-replacement therapies.”
References: Collinson, Adam, Amanda J. Collier, Natasha P. Morgan, Arnold R. Sienerth, Tamir Chandra, Simon Andrews, and Peter J. Rugg-Gunn. “Deletion of the Polycomb-Group Protein EZH2 Leads to Compromised Self-Renewal and Differentiation Defects in Human Embryonic Stem Cells.” Cell Reports 17, no. 10 (2016): 2700-714. doi:10.1016/j.celrep.2016.11.032. Research funding: The Wellcome Trust, Medical Research Council, Biotechnology and Biological Sciences Research Council. Adapted from press release by Babraham Institute.
Syphilis has plagued humankind for over 500 years. After the first reported outbreaks struck Europe in 1495, the disease spread rapidly to other continents and swelled to a global pandemic. When treatment with the antibiotic penicillin became available in the mid-twentieth century, infection rates started to decrease dramatically. Strikingly, however, infection with the bacteria Treponema pallidum subsp. pallidum (TPA) has been re-emerging globally in the last few decades; more than 10 million cases are reported annually. Yet the reason for the resurgence of this sexually transmitted infection remains poorly understood.
According to the authors of the paper, little is known about the patterns of genetic diversity in current infections or the evolutionary origins of the disease. Because clinical samples from syphilis patients only contain low quantities of treponemal DNA and the pathogen is difficult to culture in the laboratory, researchers from the University of Zurich decided in 2013 to apply DNA capture and whole-genome sequencing techniques, as used by colleagues at the University of Tübingen, to ancient DNA samples. The team collected 70 clinical and laboratory samples of syphilis, yaws, and bejel infections from 13 countries spread across the globe. Like syphilis bacteria, the closely related subspecies Treponema pallidum subsp. pertenue (TPE) and Treponema pallidum subsp. endemicum (TEN), which cause yaws and bejel, are transmitted through skin contact and show similar clinical manifestations.
Immunofluorescence photomicrograph of Treponema bacteria in human tissue. Credit: Steven J. Norris, UTHealth McGovern Medical School, Houston/USA
By using genome-wide data, the researchers were able to reconstruct a phylogenetic tree showing a clear separation between the TPA lineage and the TPE/TEN lineage. “There have been many questions regarding the origin of syphilis since its appearance on the world stage 500 years ago. By combining an evolutionary and an epidemiological approach, we were able to decipher the genetic relation between strains infecting individuals today, and also trace the emergence of a pandemic cluster with high frequency of antibiotic resistance”, says Homayoun C. Bagheri, former professor at the UZH Institute for Evolutionary Biology and Environmental Studies.
Current syphilis infections predominantly due to resistant strains from a pandemic cluster. The genomic analyses show the emergence of a pandemic cluster named SS14-Ω, which is present in contemporary infections around the globe and distinct from the cluster comprising the well-studied Nichols reference strain. “Our findings highlight the need to study more extensively the predominant strain type in the contemporary epidemic”, states Natasha Arora, researcher at the Zurich Institute of Forensic Medicine and first author of the study published in Nature Microbiology.
An evolutionary finding of epidemiological relevance is that the SS14-Ω cluster originated from a strain ancestor in the mid-20th century – after the discovery of antibiotics. The worrying aspect of this pandemic cluster is its high resistance to azithromycin, a second-line drug that is widely used to treat sexually transmitted infections. Natasha Arora adds: “The good news is that, so far, no Treponema strains have been detected that are resistant to penicillin, the first-line antibiotic for syphilis treatment.”
Co-author Philipp Bosshard from the University Hospital Zurich is continuing to collect Swiss patient samples in order to further study the clinical aspects of the work. The researchers are convinced that this type of analysis will open new opportunities to develop a comprehensive understanding of the epidemiology of syphilis – a devastating disease that persists to this day, despite the availability of treatment.
Citation: “Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster”. Natasha Arora, Verena J. Schuenemann, Günter Jäger, Alexander Peltzer, Alexander Seitz, Alexander Herbig, Michal Strouhal, Linda Grillová, Leonor Sánchez-Busó, Denise Kühnert, Kirsten I. Bos, Leyla Rivero Davis, Lenka Mikalová, Sylvia Bruisten, Peter Komericki, Patrick French, Paul R. Grant, María A. Pando, Lucía Gallo Vaulet, Marcelo Rodríguez Fermepin, Antonio Martinez, Arturo Centurion Lara, Lorenzo Giacani, Steven J. Norris, David Šmajs, Philipp P. Bosshard, Fernando González-Candelas, Kay Nieselt, Johannes Krause & Homayoun C. Bagheri. Nature Microbiology 2016 vol: 2 pp: 16245 DOI: 10.1038/nmicrobiol.2016.245
Autism spectrum disorder is caused by a variety of factors, both genetic and environmental. But a new study led by UCLA scientists provides further evidence that the brains of people with the disorder tend to have the same “signature” of abnormalities at the molecular level.
The scientists analyzed 251 brain tissue samples from nearly 100 deceased people — 48 who had autism and 49 who didn’t. Most of the samples from people with autism showed a distinctive pattern of unusual gene activity. The findings, published in Nature, confirm and extend the results of earlier, smaller studies, and provide a clearer picture of what goes awry, at the molecular level, in the brains of people with autism.
Brains typically have a standard pattern for which genes are active and which are inactive (left). In the brains of people with autism (right), genes don’t follow that pattern, but they do have their own consistent patterns from one brain to the next. Credit: Neelroop Parikshak/UCLA Health
“This pattern of unusual gene activity suggests some possible targets for future autism drugs,” said Dr. Daniel Geschwind, the paper’s senior author and UCLA’s Gordon and Virginia MacDonald Distinguished Professor of Human Genetics. “In principle, we can use the abnormal patterns we’ve found to screen for drugs that reverse them — and thereby hopefully treat this disorder.”
According to the Centers for Disease Control and Prevention, about 1.5 percent of children in the U.S. have autism; the disorder is characterized by impaired social interactions and other cognitive and behavioral problems. In rare cases, the disorder has been tied to specific DNA mutations, maternal infections during pregnancy or exposures to certain chemicals in the womb. But in most cases, the causes are unknown.
In a much-cited study in Nature in 2011, Geschwind and colleagues found that key regions of the brain in people with different kinds of autism had the same broad pattern of abnormal gene activity. More specifically, researchers noticed that the brains of people with autism didn’t have the “normal” pattern for which genes are active or inactive that they found in the brains of people without the disorder. What’s more, the genes in brains with autism weren’t randomly active or inactive in these key regions, but rather had their own consistent patterns from one brain to the next — even when the causes of the autism appear to be very different.
The discovery suggested that different genetic and environmental triggers of autism disorders mostly lead to disease via the same biological pathways in brain cells. In the new study, Geschwind and his team analyzed a larger number of brain tissue samples and found the same broad pattern of abnormal gene activity in areas of the brain that are affected by autism.
“Traditionally, few genetic studies of psychiatric diseases have been replicated, so being able to confirm those initial findings in a new set of patients is very important,” said Geschwind, who also is a professor of neurology and psychiatry at the David Geffen School of Medicine at UCLA. “It strongly suggests that the pattern we found applies to most people with autism disorders.”
The team also looked at other aspects of cell biology, including brain cells’ production of molecules called long non-coding RNAs, which can suppress or enhance the activity of many genes at once. Again, the researchers found a distinctive abnormal pattern in the autism disorder samples.
Further studies may determine which abnormalities are drivers of autism, and which are merely the brain’s responses to the disease process. But the findings offer some intriguing leads about how the brains of people with autism develop during the first 10 years of their lives. One is that, in people with the disorder, genes that control the formation of synapses the ports through which neurons send signals to each other are abnormally quiet in key regions of the brain. During the same time frame, genes that promote the activity of microglial cells, the brain’s principal immune cells, are abnormally busy. This could mean that the first decade of life could be a critical time for interventions to prevent autism.
The study also confirmed a previous finding that in the brains of people with autism, the patterns of gene activity in the frontal and temporal lobes are almost the same. In people who don’t have autism, the two regions develop distinctly different patterns during childhood. The new study suggests that SOX5, a gene with a known role in early brain development, contributes to the failure of the two regions to diverge in people with autism.
Citation:“Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism”. Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Manuel Irimia, Gokul Ramaswami, Michael J. Gandal, Christopher Hartl, Virpi Leppa, Luis de la Torre Ubieta, Jerry Huang, Jennifer K. Lowe, Benjamin J. Blencowe, Steve Horvath & Daniel H. Geschwind. Nature 2016. DOI: 10.1038/nature20612 Research funding: National Institutes of Health. Adapted from press release by UCLA.
A blood test could predict how well small-cell lung cancer (SCLC) patients will respond to treatment, according to new research published in Nature Medicine today. Scientists, based at the Cancer Research UK Manchester Institute at The University of Manchester, isolated tumor cells that had broken away from main cancer known as circulating tumor cells (CTCs) – from the blood of 31 patients with this aggressive form of the disease.When researchers analyzed these cells, they discovered that patterns of genetic faults measured before treatment were linked to how well and how long a patient might respond to chemotherapy.
Obtaining a tumor sample from lung cancer patients using an operation, known as a biopsy, can be difficult because the tumor is hard to reach and samples are often too small to reveal useful clues on how best to treat patients. Liquid biopsies offer an alternative to taking tumor samples, providing a snapshot of the disease from a blood sample.
The team also investigated the genetic changes that occurred in patients who initially responded well to treatment but later relapsed. The pattern in these cells was different from patients who didn’t respond well to chemotherapy, suggesting different mechanisms of drug resistance had developed.
Lead researcher Professor Caroline Dive, based at the Cancer Research UK Manchester Institute, said: “Our study reveals how blood samples could be used to anticipate how lung cancer patients may respond to treatments”. Unfortunately, we have very few treatment options for patients with SCLC and none at all for those whose cancer is resistant to chemotherapy. “By identifying differences in the patterns of genetic faults between patients, we now have a starting point to begin to understand more about how drug resistance develops in patients with this aggressive form of lung cancer.”
Dr. Emma Smith, Cancer Research UK’s science information manager, said: “Lung cancer causes more than one in five of all cancer deaths in the UK and it’s vital that we find effective new treatments to fight the disease and save more lives. “These liquid biopsies are an incredibly exciting area of research. Studies like this help build a bigger picture of the disease, pointing the way to developing new treatments that are urgently needed for people with lung cancer.”
Citation: “Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer”. Louise Carter, Dominic G Rothwell, Barbara Mesquita, Christopher Smowton, Hui Sun Leong, Fabiola Fernandez-Gutierrez, Yaoyong Li, Deborah J Burt, Jenny Antonello, Christopher J Morrow, Cassandra L Hodgkinson, Karen Morris, Lynsey Priest, Mathew Carter, Crispin Miller, Andrew Hughes, Fiona Blackhall, Caroline Dive& Ged Brady. Nature Medicine 2016. DOI: http://dx.doi.org/10.1038/nm.4239 Adapted from press release by the University of Manchester.
Meningiomas are the most common primary brain tumors, but the term encompasses over a dozen subtypes that range from benign to highly aggressive. Rhabdoid meningiomas are classified as highly aggressive due to their high rates of recurrence and mortality, but the experience and outcomes for patients with this rare form of brain tumor vary widely. Researchers from Brigham and Women’s Hospital, in collaboration with colleagues at Massachusetts General Hospital, have identified genetic mutations in this form of brain cancer that can distinguish aggressive rhabdoid meningiomas from more benign forms using routine laboratory tests. The work is published in the journal Neuro-Oncology.
BAP1 immunohistochemistry of a rhabdoid meningioma
sample from a patient that carries a BAP1 mutation. The
protein is completely lost in the tumor cells but is still fully
maintained in normal blood vessel cells and in infiltrating
fibroblasts and immune cells.
Credit: Sandro Santagata, Brigham and Women’s Hospital
Usually, rhabdoid meningiomas are classified based on physical appearance and characteristics, but these enigmatic tumors can be difficult for pathologists to accurately classify. To find a molecular fingerprint that could help identify rhabdoid meningioma, Santagata and his colleagues sequenced 560 cancer-related genes from 14 meningiomas. In one sample, the team detected a mutation in the BAP1 gene along with telltale physical features (such as the shape of the tumor cells) of rhabdoid meningioma. Previous studies had found that people with inherited mutations in the BAP1 gene that cause a loss of BAP1 protein are prone to a tumor predisposition syndrome – a condition that puts them at a very high risk of developing several kinds of tumors including tumors in the eye, lung, kidney and elsewhere. But primary brain tumors had not been associated with the syndrome before.
The team went on to analyze samples from 47 patients with rhabdoid meningiomas as well as 265 additional meningiomas of diverse subtypes and grades. None of the non-rhabdoid meningiomas had a loss of BAP1. However, five of the 47 patients with rhabdoid meningiomas did have mutations or deletions affecting BAP1. These patients had poor clinical outcomes: two died of the disease and two had multiple cases of recurrence; clinical follow-up information was not available for the fifth. For those patients with intact BAP1, average time of disease progression was 116 months; for the patients with BAP1 mutations, it was only 26 months.
The presence or absence of BAP1 can be monitored with a simple and inexpensive test known as immunohistochemistry – in which a tissue sample is collected and stained for a particular protein. This approach is currently in routine use for characterizing samples of an eye cancer known as uveal melanoma and a tumor that arises from the linings of the chest and abdomen known as mesothelioma – forms of cancer tied to the tumor predisposition syndrome.
The number of cases of rhabdoid meningioma studied in this work was small; larger studies will be needed to determine the prevalence of BAP1 mutations in rhabdoid meningiomas and to assess the impact of their detection on clinical care. However, the new work strongly suggests that a careful assessment of family history is a critical for patients who develop rhabdoid meningiomas and that patients with BAP1 negative tumors may warrant more careful observation and focused care.
“Testing for BAP1 in rhabdoid meningiomas could be performed routinely and at a low cost, with the potential to change the course of clinical care and avoid overtreatment or to identify those who may need more aggressive therapy,” said Santagata. “We hope that this new work will offer insights for clinicians and patients alike as they seek more information on these tumors.” Citation: “Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas”. Ganesh M. Shankar, Malak Abedalthagafi, Rachael A. Vaubel, Parker H. Merrill, Naema Nayyar, Corey M. Gill, Ryan Brewster, Wenya Linda Bi, Pankaj K. Agarwalla, Aaron R. Thorner, David A. Reardon, Ossama Al-Mefty, Patrick Y. Wen, Brian M. Alexander, Paul van Hummelen, Tracy T. Batchelor, Keith L. Ligon, Azra H. Ligon, Matthew Meyerson, Ian F. Dunn, Rameen Beroukhim, David N. Louis, Arie Perry, Scott L. Carter, Caterina Giannini, William T. Curry Jr, Daniel P. Cahill, Frederick G. Barker II, Priscilla K. Brastianos and Sandro Santagata. Neuro-Oncology. 2016 pp: now235 DOI: http://dx.doi.org/10.1093/neuonc/now235 Research funding: Brain Science Foundation, Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research, King Abdulaziz City for Science and Technology Saudi Arabia, Ludwig Center at Harvard, National Institutes of Health, Susan G. Komen Adapted from press release by Brigham and Women’s Hospital.
A research team at the Krembil Research Institute has discovered that a signaling pathway which controls blood vessel development in the brain has the ability to stop brain tumor formation in animal models of medulloblastoma, the most common malignant brain tumor diagnosed in children.
The findings, published in the journal eLife, are the first to show that blocking a signaling pathway called Norrin/Frizzled4 (Fzd4) drives changes in the support structures that surround pre-cancer cells and promotes medulloblastoma development in subjects that are genetically susceptible to the disease. Researchers found that blocking the Norrin/Fzd4 signal created more opportunities to form pre-cancerous growths and speed up tumour initiation. This work also suggests that an activated pathway may therefore block tumour formation.
“Our study brings a new dimension to our understanding of Medulloblastoma,” says Dr. Valerie Wallace, principal investigator of the study, Norrin/Frizzled4 Signaling in the Preneoplastic Niche Blocks Medulloblastoma Initiation, and Co-Director of the Donald K. Johnson Eye Institute.
The research, which was carried out in large part by Dr. Erin Bassett and Mr. Nicholas Tokarew, was initiated at the Ottawa Hospital Research Institute and continued at the Krembil Research Institute after Dr. Wallace relocated to Toronto. The discovery came from replication of a human condition called Gorlin Syndrome in lab experiments. People with Gorlin Syndrome have one copy of a tumour-suppressing gene instead of two, which makes them susceptible to medulloblastoma.
The team’s next step will be to investigate how the blood vessels impacted by Norrin/Fzd4 signaling communicate with pre-cancerous cells to make them more likely to become malignant.
Citation: Bassett, Erin A., Nicholas Tokarew, Ema A. Allemano, Chantal Mazerolle, Katy Morin, Alan J. Mears, Brian McNeill et al. “Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.” eLife 5 (2016): e16764. DOI: http://dx.doi.org/10.7554/eLife.16764 Research funding: Canadian Cancer Society, Cancer Research Society Adapted from press release by University Health Network Ca
A research effort at the Centre for Genomic Regulation in Barcelona, Spain, reveals new molecular mechanisms of Huntington’s disease. The results, published in The Journal of Clinical Investigation, question the approaches used up to now for treatment of the disease. They also point to messenger RNA as a key pathogenic component that will make it possible to define new therapeutic strategies.
Fluorescent detection of foci in red fibroblasts of patients with Huntington’s disease. Up: cells showing mutated RNA foci. Down: Cells with blocked RNA do not show foci. Credit: Centre for Genoic Regulation
Huntington’s disease is a neurodegenerative disease that is presently incurable. Scientists around the world are researching its causes and molecular processes in the attempt to find a treatment. Huntington’s disease is caused by the excessive repetition of a nucleotide triplet (CAG) in the Huntingtin gene. The number of CAG repetitions varies from person to person. Healthy individuals can have up to 36 repetitions. Nevertheless, as of 36 repetitions, Huntington’s disease develops. The direct consequence of this excess of repetitions is the synthesis of a mutated protein–different from what would be obtained without the additional CAG repetitions–which has been considered the main cause of the disease for the past 20 years.
The research by a group of scientists from the Centre for Genomic Regulation (CRG) led by Eulàlia Martí, in cooperation with researchers from the University of Barcelona (UB) and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), has brought to light new information on the molecular mechanisms that cause Huntington’s disease, and defines new pathways to therapy discovery.
“What we have observed in our study is that the mutated fragment acting as a conveyor–the so-called messenger RNA–is key in the pathogenesis,” says Dr. Eulàlia Martí, lead author of the research project, together with Xavier Estivill, and acting group leader of the Genes and Disease laboratory at the Centre for Genomic Regulation. “The research on this disease being done by most groups around the world seeking new therapeutic strategies focuses on trying to prevent expression of the mutated protein. Our work suggests that blocking the activity of messenger RNA (the “conveyor”), would be enough to revert the alterations associated with Huntington’s disease. We hope this will contribute to improving the strategies in place to find a cure,” states the researcher.
Going deeper in molecular mechanisms enables progress to future applications. This work underscores the importance of rethinking the mechanisms behind illnesses in order to find new treatments. The work of scientists at the CRG has helped explore the molecular mechanisms that cause the disease. Now, their results will contribute to better delimit research efforts towards a cure.
As opposed to most other research groups, Eulàlia Martí’s team has sought to identify whether the problem resided in the messenger RNA – which would be the copy responsible for manufacturing the protein – or in the resulting protein. Prior work indicated that mRNA produced, in addition to defective protein, other damages. This previous work was the starting point for Martí and her fellow researchers, who have finally demonstrated that mRNA has a key role in the pathogenesis of Huntington’s chorea. “The research we have just published points to RNA’s clear role in Huntington’s disease. This information is very important in translational research to take on new treatments,” says the researcher.
More in-depth studies on these mechanisms are yet to be done. For example, research must explore whether it will be possible to revert the effects of Huntington’s disease in patients, just as researchers have demonstrated in mouse models. It also remains to be seen whether the proposal of the CRG researchers can be used in a preventive way, as the disease does not generally appear until after 40 years of age (in humans). Despite the remaining gaps, the published work makes for a key step in knowledge of the mechanisms of this neurodegenerative disease that, as of today, remains incurable.
Citation: Rué, Laura, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer et al. “Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels.” The Journal of Clinical Investigation 126, no. 11 (2016). DOI: http://dx.doi.org/10.1172/JCI83185 Adapted from press release by Centre for Genomic Regulation
Sudden death strikes approximately 11,000 people under age 45 in the U.S. every year, leaving living relatives with troubling questions about their own risk. Unfortunately, with many conditions—such as sudden infant death syndrome (SIDS) and sudden cardiac death (SCD)—the cause of death is not always apparent after a traditional clinical autopsy.
Now a new study led by scientists at The Scripps Research Institute (TSRI) and the Scripps Translational Science Institute (STSI) suggests that “molecular autopsies” may be valuable in detecting gene mutations responsible for a sudden death. The research, while preliminary, could help doctors alert living family members to hidden health conditions.
“The key takeaway is that molecular autopsy, when performed in a prospective and family-based manner, can reveal the genetic cause of sudden death in a variety of conditions and provide useful information regarding risk to living relatives,” Torkamani said.
For the study, the researchers sequenced samples from 25 sudden death cases. To assess possible inherited mutations, the team also sequenced samples from the deceased patients’ parents in nine of the cases.
This analysis provided clues that weren’t apparent in traditional clinical autopsies. In four cases, the researchers found that a genetic mutation was a “likely” cause of death, and they found six more cases where a mutation was a “plausible” cause of death. In seven cases, a mutation was found to be a “speculative” cause of death.
Overall, molecular autopsies uncovered a likely or plausible cause of death in 40 percent of cases. Interestingly, many of the findings were variants of genes inherited from relatives who had not suffered from the syndrome.
The researchers believe identifying possible genetic mutations behind sudden death could help doctors and family members plan for clinical follow-ups, preventative measures and active surveillance to watch for symptoms—even in cases where the mutation was just a “speculative” cause of death.
The researchers said larger studies are needed to collect enough data to provide living relatives with a better idea of their risk.