GN/ Longevity gene from naked mole rats extends lifespan of mice
Genetics biweekly vol.44, 5th September — 19th September
TL;DR
- In a groundbreaking endeavor, researchers have successfully transferred a longevity gene from naked mole rats to mice, resulting in improved health and an extension of the mouse’s lifespan. The research opens exciting possibilities for unlocking the secrets of aging and extending human lifespan.
- By adding synergistic self-adjuvanting properties to Covid-19 RNA vaccines, researchers showed they could significantly boost the immune response generated in mice.
- In many animals, including ants, the blood-brain barrier (BBB) ensures normal brain function by controlling the movement of various substances in and out of the brain. Now, researchers have made the unexpected discovery that the BBB in carpenter ants plays an active role in controlling behavior that’s essential to the function of entire ant colonies. The key is production in the BBB of a particular hormone-degrading enzyme.
- Selective targeting of cancerous cells poses major clinical challenges during cancer therapy. However, this limitation can be overcome by using bioengineered bacteria with highly optimized chemical modifications. A recent study demonstrates the use of chemically modified purple photosynthetic bacteria for the successful detection and elimination of colon cancer cells in a mouse model. The study also sheds light on the underlying mechanism of action.
- Patescibacteria are a group of puzzling, tiny microbes whose manner of staying alive has been difficult to fathom. Scientists can cultivate only a few types, yet these bacteria are a diverse group found in many environments. In a new study, researchers present the first glimpse into the molecular mechanisms behind their relationship with their host cells. They also share details gleaned from fluorescent, time-lapse microsopic imaging of these bacteria as they bud and send out swarms of tiny progeny, only a fraction of which are able to establish a host relationship.
- A team of researchers has revealed that the Dumpy protein, a component of extracellular matrices — or ECM — is the key factor in regulating the stereotypic origami-like folding of wing-cell sheets. Their findings that wing cells never divide during folding nor do they exhibit spatially distinct behaviors suggest how external cues can create consistent 3D tissue structures.
- Scientists have identified a key part of a mechanism that annotates genetic information before it is passed from fathers to their offspring. The findings shed new light on genomic imprinting, a fundamental, biological process in which a gene from one parent is switched off while the copy from the other parent remains active. Errors in imprinting are linked to a host of diseases, such as the rare disease Silver-Russell syndrome along with certain cancers and diabetes.
- A research team has discovered a new ribozyme that can label RNA molecules in living cells.
- Researchers have developed a new imaging technique to observe active gene expression in real time. They found that four molecules work together to control the timing of each stage of the C. elegans worm’s development. This timekeeping process could provide important clues about the natural rhythm of development in humans and other animals.
- A new study has shown that a subtype of avian flu virus, endemic in poultry farms in China, is undergoing mutational changes, which could increase the risk of the disease being passed on to humans.
- And more!
Overview
Genetic technology is defined as the term which includes a range of activities concerned with the understanding of gene expression, advantages of natural genetic variation, modifying genes and transferring genes to new hosts. Genes are found in all living organisms and are transferred from one generation to the next. Gene technology encompasses several techniques including marker-assisted breeding, RNAi and genetic modification. Only some gene technologies produce genetically modified organisms.
Modern genetic technologies like genome editing would not be possible without all the previous generations of genetic technologies that have enabled scientists to discover what genes are, what they do and how DNA can be modified to add, remove or replace genes. You can find major genetic technologies development milestones via the link.
Gene Technology Market
- The valuation of the genetic engineering market is projected to escalate to USD 6.90 MN by the end of 2027.
- Global Genetic Engineering Market is projected to grow at 12.48% CAGR during the assessment period (2017–2027).
- North America holds the largest share in the global genetic engineering market, followed by Europe and the Asia Pacific, respectively.
- Another research provider, MarketsandMarkets, forecasts the genome editing, genome engineering market to grow from USD 3.19 billion in 2017 to USD 6.28 billion by 2022, at a compounded annual growth rate (CAGR) of 14.5% during the forecast period. The key factors propelling market growth are rising government funding and growth in the number of genomics projects, high prevalence of infectious diseases (like COVID-19) and cancer, technological advancements, increasing production of genetically modified (GM) crops, and growing application areas of genomics.
Latest News & Research
Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice
by Zhihui Zhang, Xiao Tian, J. Yuyang Lu, Kathryn Boit, et al in Nature
In a groundbreaking endeavor, researchers at the University of Rochester have successfully transferred a longevity gene from naked mole rats to mice, resulting in improved health and an extension of the mouse’s lifespan.
Naked mole rats, known for their long lifespans and exceptional resistance to age-related diseases, have long captured the attention of the scientific community. By introducing a specific gene responsible for enhanced cellular repair and protection into mice, the Rochester researchers have opened exciting possibilities for unlocking the secrets of aging and extending human lifespan.
“Our study provides a proof of principle that unique longevity mechanisms that evolved in long-lived mammalian species can be exported to improve the lifespans of other mammals,” says Vera Gorbunova, the Doris Johns Cherry Professor of biology and medicine at Rochester. Gorbunova, along with Andrei Seluanov, a professor of biology, and their colleagues, report in a study that they successfully transferred a gene responsible for making high molecular weight hyaluronic acid (HMW-HA) from a naked mole rat to mice. This led to improved health and an approximate 4.4 percent increase in median lifespan for the mice.
Naked mole rats are mouse-sized rodents that have exceptional longevity for rodents of their size; they can live up to 41 years, nearly ten times as long as similar-size rodents. Unlike many other species, naked mole rats do not often contract diseases — including neurodegeneration, cardiovascular disease, arthritis, and cancer — as they age. Gorbunova and Seluanov have devoted decades of research to understanding the unique mechanisms that naked mole rats use to protect themselves against aging and diseases.
The researchers previously discovered that HMW-HA is one mechanism responsible for naked mole rats’ unusual resistance to cancer. Compared to mice and humans, naked mole rats have about ten times more HMW-HA in their bodies. When the researchers removed HMW-HA from naked mole rat cells, the cells were more likely to form tumors. Gorbunova, Seluanov, and their colleagues wanted to see if the positive effects of HMW-HA could also be reproduced in other animals.
The team genetically modified a mouse model to produce the naked mole rat version of the hyaluronan synthase 2 gene, which is the gene responsible for making a protein that produces HMW-HA. While all mammals have the hyaluronan synthase 2 gene, the naked mole rat version seems to be enhanced to drive stronger gene expression.
The researchers found that the mice that had the naked mole rat version of the gene had better protection against both spontaneous tumors and chemically induced skin cancer. The mice also had improved overall health and lived longer compared to regular mice. As the mice with the naked mole rat version of the gene aged, they had less inflammation in different parts of their bodies — inflammation being a hallmark of aging — and maintained a healthier gut. While more research is needed on exactly why HMW-HA has such beneficial effects, the researchers believe it is due to HMW-HA’s ability to directly regulate the immune system.
The findings open new possibilities for exploring how HMW-HA could also be used to improve lifespan and reduce inflammation-related diseases in humans.
“It took us 10 years from the discovery of HMW-HA in the naked mole rat to showing that HMW-HA improves health in mice,” Gorbunova says. “Our next goal is to transfer this benefit to humans.”
They believe they can accomplish this through two routes: either by slowing down degradation of HMW-HA or by enhancing HMW-HA synthesis.
“We already have identified molecules that slow down hyaluronan degradation and are testing them in pre-clinical trials,” Seluanov says. “We hope that our findings will provide the first, but not the last, example of how longevity adaptations from a long-lived species can be adapted to benefit human longevity and health.”
Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA
by Bowen Li, Allen Yujie Jiang, Idris Raji, et al in Nature Biomedical Engineering
RNA vaccines against Covid-19 have proven effective at reducing the severity of disease. However, a team of researchers at MIT is working on making them even better. By tweaking the design of the vaccines, the researchers showed that they could generate Covid-19 RNA vaccines that produce a stronger immune response, at a lower dose, in mice.
Adjuvants are molecules commonly used to increase the immune response to vaccines, but they haven’t yet been used in RNA vaccines. In this study, the MIT researchers engineered both the nanoparticles used to deliver the Covid-19 antigen, and the antigen itself, to boost the immune response, without the need for a separate adjuvant.
If further developed for use in humans, this type of RNA vaccine could help to reduce costs, reduce the dosage needed, and potentially lead to longer-lasting immunity. The researchers’ tests also showed that when delivered intranasally, the vaccine induced a strong immune response when compared to the response elicited by traditional, intramuscular vaccination.
“With intranasal vaccination, you might be able to kill Covid at the mucus membrane, before it gets into your body,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study. “Intranasal vaccines may also be easier to administer to many people, since they don’t require an injection.”
The researchers believe that the effectiveness of other types of RNA vaccines that are now in development, including vaccines for cancer, could be improved by incorporating similar immune-stimulating properties. Former MIT postdoc Bowen Li, who is now an assistant professor at the University of Toronto; graduate student Allen Jiang; and former MIT postdoc Idris Raji, who was a research fellow at Boston Children’s Hospital, are the lead authors of the new study. The research team also includes Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, and several other MIT researchers.
RNA vaccines consist of a strand of RNA that encodes a viral or bacterial protein, also called an antigen. In the case of Covid-19 vaccines, this RNA codes for a segment of the virus’s spike protein. That RNA strand is packaged in a lipid nanoparticle carrier, which protects the RNA from being broken down in the body and helps it get into cells. Once delivered into cells, the RNA is translated into proteins that the immune system can detect, generating antibodies and T cells that will recognize the protein if the person later becomes infected with the SARS-CoV-2 virus.
The original Covid-19 RNA vaccines developed by Moderna and Pfizer/BioNTech provoked strong immune responses, but the MIT team wanted to see if they could make them more effective by engineering them to have immune stimulatory properties.
In this study, the researchers employed two different strategies to boost the immune response. For the first, they focused on a protein called C3d, which is part of an arm of the immune response known as the complement system. This set of proteins helps the body fight off infection, and C3d’s role is to bind to antigens and amplify the antibody response to those antigens. For many years, scientists have been evaluating the use of C3d as a molecular adjuvant for vaccines made from proteins, such as the DPT vaccine.
“With the promise of mRNA technologies being realized with the Covid vaccines, we thought that this would be a fantastic opportunity to see if C3d might also be able to play a role as an adjuvant in mRNA vaccine systems,” Jiang says.
To that end, the researchers engineered the mRNA to encode the C3d protein fused to the antigen, so that both components are produced as one protein by cells that receive the vaccine. In the second phase of their strategy, the researchers modified the lipid nanoparticles used to deliver the RNA vaccine, so that in addition to helping with RNA delivery, the lipids also intrinsically stimulate a stronger immune response.
To identify lipids that would work best, the researchers created a library of 480 lipid nanoparticles with different types of chemistries. All of these are “ionizable” lipids, which become positively charged when they enter acidic environments. The original Covid RNA vaccines also included some ionizable lipids because they help the nanoparticles to self-assemble with RNA and they help target cells to take up the vaccine.
“We understood that nanoparticles themselves could be immunostimulatory, but we weren’t quite sure what the chemistry was that was needed to optimize that response. So instead of trying to make the perfect one, we made a library and evaluated them, and through that we identified some chemistries that seemed to improve their response,” Anderson says.
The researchers tested their new vaccine, which included both RNA-encoded C3d and a top-performing ionizable lipid identified from their library screen, in mice. They found that mice injected with this vaccine produced 10 times more antibodies than mice given unadjuvanted Covid RNA vaccines. The new vaccine also provoked a stronger response among T cells, which play important roles in combating the SARS-CoV-2 virus.
“For the first time, we’ve demonstrated a synergistic boost in immune responses by engineering both the RNA and its delivery vehicles,” Li says. “This prompted us to investigate the feasibility of administering this new RNA vaccine platform intranasally, considering the challenges presented by the mucociliary blanket barrier in the upper airways.”
When the researchers delivered the vaccine intranasally, they observed a similarly strong immune response in the mice. If developed for use in people, an intranasal vaccine could potentially offer enhanced protection against infection because it would generate an immune response within the mucosal tissues that line the nasal passages and lungs. Because self-adjuvanting vaccines elicit a stronger response at a lower dose, this approach could also help to reduce the cost of vaccine doses, which might allow them to reach more people, especially in developing nations, the researchers say.
Hormonal gatekeeping via the blood-brain barrier governs caste-specific behavior in ants
by Linyang Ju, Karl M. Glastad, Lihong Sheng, Janko Gospocic, Callum J. Kingwell, Shawn M. Davidson, Sarah D. Kocher, Roberto Bonasio, Shelley L. Berger in Cell
In many animals, including ants, the blood-brain barrier (BBB) ensures normal brain function by controlling the movement of various substances in and out of the brain. Now, researchers have made the unexpected discovery that the BBB in carpenter ants plays an active role in controlling behavior that’s essential to the function of entire ant colonies. The key is production in the BBB of a particular hormone-degrading enzyme.
“In these ants, the BBB produces a special version of the enzyme Juvenile hormone esterase (Jhe), which degrades Juvenile Hormone (JH3),” says Karl Glastad, the co-lead author along with Linyang Ju, both in the lab of senior author Shelley Berger in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Typically, Jhe enzymes are secreted into the hemolymph (insect blood); however the copy produced by the ant BBB is retained in the cells of the BBB where it controls the amount of JH3 hormone entering the brain of the worker ant,” Ju says.
JH3 hormone is known to promote foraging among social insect workers. Different types of worker ants within the same colony do very different “jobs.” The new findings show that this results, in part, from different levels of the JH3-degrading enzyme in their BBB, leading to different levels of the hormone JH3 in the brain.
The finding underscores how a single protein expressed in the right place at the right time can have major effects on individual behaviors underlying complex societies, the researchers say. And it isn’t just ants; the researchers already have evidence that similar mechanisms may play a role in mouse behavior, too.
The researchers made the discovery after applying single-cell RNA sequencing to understand differences in gene activity across cells in the brain in two ant behavioral castes: foragers and soldiers. Their analysis revealed that the gene encoding Jhe, the degrading enzyme for the hormone JH3, was found only in BBB cells. It also showed striking differences between the BBB cells of foragers and soldiers. They wanted to know more about what it meant for ant behavior.
Their studies show that intentional manipulation of the level of the Jhe degrading enzyme reprograms the brain and complex behaviors that differ between ant castes, switching the soldier caste to foraging behavior. They went on to show in Drosophila fruit flies that Jhe enzyme is naturally outside of cells. When they made the fly BBB express the ant version of the Jhe enzyme, they saw behavioral changes similar to those observed in the ants.
“Differences in expression of this single enzyme [Jhe] between the BBB of different castes control the hugely important decision to forage or to stay inside the nest for defense as soldiers and can even reprogram flies to change food-seeking behavior,” Glastad said.
To see if similar mechanisms apply in other animals, the researchers also analyzed published data from a panel of mouse endothelial cells, including those from the mouse BBB. They found that mouse BBB cells also expressed several hormone-degrading enzymes at higher levels than any other endothelial cell type. Most notably, these include enzymes that degrade the hormone testosterone.
“This suggests that gating hormone entry into the brain by the BBB is a function extending well beyond ants and that gating a hormone differentially between behavioral conditions as seen in ants may exist in other organisms, including mammals,” Berger says. In future studies, the researchers say they want to learn more about the origin and prevalence of this mechanism and whether it is a convergent strategy to control behavior outside of ants.
Cancer immunotheranostics using bioactive nanocoated photosynthetic bacterial complexes
by Sheethal Reghu, Seigo Iwata, Satoru Komatsu, Takafumi Nakajo, Eijiro Miyako in Nano Today
Targeting malignant tumors with high precision is challenging for biomedical researchers. However, this scenario is likely to witness a paradigm shift in the near future, through the use of specially engineered bacteria, that can eliminate malignant cells efficiently.
Using bacteria to target cancer cells, or bacterial therapy, can be further enhanced through genetic engineering and nanotechnology. However, its efficacy may be hindered due to technical constraints and the potential development of antibiotic resistance. Hence, it is crucial to achieve the moderate yet effective chemical modification of bacteria for improved biocompatibility and functionality, such that their medical abilities are not compromised.
Recently, certain types of purple photosynthetic bacteria (PPSB) have come into limelight for their potential to address the challenges of bacterial therapy. Exploring this further, a study reports the use of chemically modified PPSB for detecting and eliminating hard-to-eradicate cancerous cells in a mouse model.
The study, led by Associate Professor Eijiro Miyako from the Japan Advanced Institute of Science and Technology (JAIST), selected Rhodopseudomonas palustris (RP) as the optimal bacterium for conducting the studies. “RP demonstrated excellent properties, such as near-infrared (NIR) fluorescence, photothermal conversion, and low cytotoxicity. It absorbs NIR light and produces free radicals — a property that can be utilized to kill cancer cells,” explains Prof. Miyako.
In an attempt to improve the therapeutic efficacy of the isolated strain, the team sought chemical modifications to alter the bacterial membranes. First, they performed membrane PEGylation, or the attachment of polyethylene glycol derivatives to the bacterial cell walls. Prior research indicates that bacterial PEGylation helps in evading host immune response and converts light energy into heat, which can then be utilized to selectively eliminate cancerous cells.
The initial results were encouraging. For instance, coating the RP membrane surface with a “Biocompatible Anchor for Membrane (BAM)” did not adversely affect RP cell viability for at least a week. Moreover, the BAM-functionalized RPs were not eliminated via phagocytosis by macrophages — cells that play a key role in the immune system’s defensive actions against bacterial invasions.
Next, the researchers attached a fluorescent “Alexa488-BSA” conjugate to the BAM-functionalized RPs, thus creating a bacterial complex with a trackable fluorescent marker. This conjugate was subsequently replaced with a “PD-L1” antibody. Prior studies have shown that cancer cells express a protein called “Programmed Cell Death Ligand 1 (PD-L1)” on their surface. PD-L1 can smoothly turn off the host defense system by binding to PD-1 receptors. This allows the cancer cells to evade immune detection and elimination. Anti-PD-L1 antibodies block this interaction, thus preventing cancer cells from bypassing immune-system-mediated destruction.
As expected, both anti-PD-L1-BAM-RP and RP, inhibited tumor growth in a murine model of colon cancer. However, anti-PD-L1-BAM-RP, BAM-RP, and RP, when excited with a laser, showed an especially dramatic anticancer effect. In fact, solid tumors vanished completely following the laser irradiation of anti-PD-L1-BAM-RP, BAM-RP, or RP that were injected into tumor-bearing mice. Further, on assessing photothermal conversion properties, both anti-PD-L1-BAM-RP and natural RP exhibited strong photothermal conversion due to the presence of light-driven bacteriochlorophyll (BChl) molecules.
Among the various bioconjugates, anti-PD-L1-BAM-RP showed the highest efficacy in the initial stage of the treatment. Moreover, it was not toxic to surrounding healthy cells or to the murine host. Subsequent experiments revealed the underlying mechanism of colon tumor annihilation in the mouse model.
“Our findings revealed that light-driven functional bacteria demonstrated effective optical and immunological functions in the murine model of colon cancer. Moreover, the NIR fluorescence of the engineered bacterial complexes was used to locate tumors, effectively paving the way for future clinical translation,” says Prof. Miyako.
He further adds, “We believe that this bacterial technology could be available for clinical trials in 10 years and have positive implications for cancer diagnosis and therapy.”
Genetic manipulation of Patescibacteria provides mechanistic insights into microbial dark matter and the epibiotic lifestyle
by Yaxi Wang, Larry A. Gallagher, Pia A. Andrade, et al in Cell
Patescibacteria are a group of puzzling, tiny microbes whose manner of staying alive has been difficult to fathom. Scientists can cultivate only a few types, yet these bacteria are a diverse group found in many environments.
The few types of Patescibacteria that researchers can grow in the lab reside on the cell surfaces of another, larger host microbe. Patescibacteria in general lack the genes required to make many molecules necessary for life, such as the amino acids that make up proteins, the fatty acids that form membranes, and the nucleotides in DNA. This has led researchers to speculate that many of them rely on other bacteria to grow.
In a study, researchers present the first glimpse into the molecular mechanisms behind the unusual Patescibacteria lifestyle. This breakthrough was made possible by the discovery of a way to genetically manipulate these bacteria, an advance that has opened a world of possible new research directions.
“While metagenomics can tell us which microbes live on and within our bodies, the DNA sequences alone do not give us insight into their beneficial or detrimental activities, especially for organisms that have never before been characterized,” said Nitin S. Baliga of the Institute for System Biology in Seattle, which contributed many computational and systems analyses to the study.
“The ability to genetically perturb Patescibacteria opens up the possibility of applying a powerful systems analysis lens to rapidly characterize the unique biology of obligate epibionts,” he added, in reference to organisms that must live on another organism to survive.
The teams behind the study, headed by Joseph Mougous’ lab in the Department of Microbiology at the University of Washington School of Medicine and the Howard Hughes Medical Institute, were interested in Patescibacteria for several reasons. They are among the many poorly understood bacteria whose DNA sequences pop up in large-scale genetic analyses of genomes found in species-rich microbial communities from environmental sources. This genetic material is referred to as “microbial dark matter” because little is known about the functions it encodes.
Microbial dark matter is likely to contain information about biochemical pathways with potential biotechnology applications, according to the paper. It also holds clues to the molecular activities that support a microbial ecosystem, as well as to the cell biology of the assorted microbial species gathered in that system.
The group of Patescibacteria analyzed in this latest research belongs to the Saccharibacteria. These live in a variety of land and water environments but are best known for inhabiting the human mouth. They have been part of the human oral microbiome at least since the Middle Stone Age and have been linked to human oral health.
In the human mouth, Saccharibacteria require the company of Actinobacteria, which serve as their hosts. To better understand the mechanisms employed by Saccharibacteria to relate with their hosts, the researchers used genetic manipulation to identify all the genes essential for a Saccharibacterium to grow.
“We are tremendously excited to have this initial glimpse into the functions of the unusual genes these bacteria harbor,” said Mougous, professor of microbiology. “By focusing our future studies on these genes, we hope to unravel the mystery of how Saccharibacteria exploit host bacteria for their growth.”
Possible host-interaction factors uncovered in the study include cell surface structures that may help Saccharibacteria attach to host cells, and a specialized secretion system that might be used for transporting nutrients. Another application of the authors’ work was the generation of Saccharibacteria cells that express fluorescent proteins. With these cells, the researchers performed time-lapse microscopic fluorescent imaging of Saccharibacteria growing with their host bacteria.
“Time-lapse imaging of Saccharibacteria-host cell cultures revealed surprising complexity in the lifecycle of these unusual bacteria,” noted S. Brook Peterson, a senior scientist in the Mougous lab.
The researchers reported that some Saccharibacteria serve as mother cells by adhering to the host cell and repeatedly budding to generate small swarmer offspring. These little ones move on to search for new host cells. Some of the progeny, in turn, became mother cells, while others appeared to interact unproductively with a host.
The researchers think that additional genetic manipulation studies will open the door to wider understanding of the roles of what they described as “the rich reserves of microbial dark matter these organisms contain” and potentially uncover yet unimagined biological mechanisms.
Spatiotemporal remodeling of extracellular matrix orients epithelial sheet folding
by Alice Tsuboi, Koichi Fujimoto, Takefumi Kondo in Science Advances
The artist in nature creates wonders of geometric patterns, as can be seen in the wings of Drosophila fruit flies just after emerging from their pupal case, which is known as eclosion. They meticulously fold into stereotypic shapes, just like in the paper-folding art of origami, invented from humanity’s innate sense of spatial awareness.
Yet, no human intervention is required when the wings fold themselves with uncanny precision according to nature’s complex blueprint. Now, a team of researchers at Kyoto University has revealed that the Dumpy protein, a component of extracellular matrices — or ECM — is the key factor in regulating the stereotypic origami-like folding of wing-cell sheets.
“Our findings are unique because they unveil how external cues can create consistent 3D tissue structures,” says first author Alice Tsuboi of KyotoU’s Graduate School of Biostudies.
According to conventional views of morphogenesis, coordinated cell behaviors, like cell division and cell shape changes, are responsible for shaping cell sheets and creating folds, such as mountain-valley patterns. Researchers may naturally assume that wing folding is controlled by these cell behaviors.
“It turns out, however, that wing cells never divide during folding nor do they exhibit spatially distinct behaviors,” adds Tsuboi.
These unexpected findings led Tsuboi’s team to investigate whether external factors might control the folding pattern. Using genetics and protein visualization techniques, the team found that Dumpy, a fibrous ECM protein, mediates the adhesion of cell sheets to their surroundings. Additionally, the spatial and temporal regulation of Dumpy deposition and destruction ensures the stereotypic folding of the wing.
“During a casual walk, I stumbled upon the eclosion of a cicada, which triggered my interest in the morphogenic mechanisms involved,” reflects Tsuboi, who saw an opportunity to examine whether an ECM-based mechanism may be a means to manufacturing diverse and controllable 3D tissue folding with coordinated cell behaviors.”
“We believe that the next step is in examining how tissues encode positional information in ECM remodeling, which may provide new insight into organ development and regeneration,” adds Tsuboi.
Establishment of paternal methylation imprint at the H19/Igf2 imprinting control region
by Ji Liao, Sangmin Song, Samuel Gusscott, Zhen Fu, Ivan VanderKolk, Brianna M. Busscher, Kin H. Lau, Julie Brind’Amour, Piroska E. Szab in Science Advances
Van Andel Institute scientists and collaborators have identified a key part of a mechanism that annotates genetic information before it is passed from fathers to their offspring.
The findings shed new light on genomic imprinting, a fundamental, biological process in which a gene from one parent is switched off while the copy from the other parent remains active. Errors in imprinting are linked to a host of diseases, such as the rare disease Silver-Russell syndrome along with certain cancers and diabetes.
“Proper imprinting is crucial for lifelong health but, despite its importance, we still lack a full understanding of the factors that regulate this vital process,” said VAI Associate Professor Piroska Szabó, Ph.D., the study’s corresponding author. “Our findings reveal an RNA mechanism that governs establishment of imprinting and illuminates why it differs between fathers and mothers.”
Our genetic information is encoded in DNA, a long, winding molecule that is tightly packed to form 23 pairs of chromosomes, half of which come from one’s father and half from one’s mother. Sperm and eggs only contain 23 single chromosomes — half of the genetic material required for life. During fertilization, they each contribute their half, resulting in a zygote with a full set of 23 pairs of chromosomes. But not all instructions in DNA are needed at the same time or in the same places. That’s where epigenetics come in. Epigenetic mechanisms annotate DNA with special chemical tags called methyl groups, which tell certain genes when to be active and when to be silent — all without changing the sequence of DNA itself.
Imprinting occurs when methyl groups are added to certain genes during either sperm or egg formation. This, in turn, is important for determining which parental copy of that gene is expressed in the offspring. To better understand the processes that govern imprinting, Szabó and colleagues focused on an imprinting control region in the DNA that regulates the Igf2 gene. Igf2 plays key roles in fetal growth and only is active in the chromosome inherited from the father. Too little methylation in the IGF2 control region in humans can result in Silver-Russell syndrome, which is marked by reduced growth and increased risk of metabolic disease.
“If the IGF2 gene’s imprinting control region from one’s father is not methylated, it can result in disease,” Szabó said.
Using genetic models and in-depth genetic sequencing, the team found that the methylation of the Igf2 control region in paternally inherited DNA is governed by an underlying RNA-based process in the male germline.
“We found earlier that RNA similarly runs through other paternally marked imprinted domains in the male germ cells, suggesting that this same process is generally true for paternal imprinting,” Szabó said. “These results suggest a more broadly applicable process, which is exciting and will need to be confirmed in subsequent studies.”
A SAM analogue-utilizing ribozyme for site-specific RNA alkylation in living cells
by Takumi Okuda, Ann-Kathrin Lenz, Florian Seitz, Jörg Vogel, Claudia Höbartner in Nature Chemistry
RNA molecules are real all-rounders. They transfer the genetic information from the DNA in the cell. They regulate the activity of genes. And some of them have a catalytic effect: just like enzymes, they enable biochemical reactions that would be difficult or impossible to occur on their own. These special RNA molecules that accelerate such reactions are called ribozymes.
The team of chemistry professor Claudia Höbartner from Julius-Maximilians-Universität (JMU) Würzburg now presents a newly discovered ribozyme called SAMURI. SAMURI can precisely modify other RNA molecules. This ability is very helpful for RNA research: “We can use such ribozymes as tools to label RNA with dyes and make it visible,” says JMU researcher Dr. Takumi Okuda. “In this way, the pathways of RNA in the cell and its interactions with other molecules can be studied even better.”
Ribozymes may also be considered for therapeutic use in the future. “We see new possible applications for ribozymes when the enzymes responsible for a specific task are missing or are no longer functional due to mutations,” says Claudia Höbartner.
What distinguishes the new ribozyme SAMURI? It modifies other RNA molecules at a precisely defined site of a specific adenine. There it attaches molecules to which, in turn, dyes or other molecules can easily be clicked in — like buckling up a seat belt. Such reactions are known as click chemistry. SAMURI also has the advantage that it is active under the same physiological conditions that prevail in living cells. This is not the case with other synthetic ribozymes.
Another special feature: SAMURI uses a new synthetic cofactor to make RNA molecules accessible for click chemistry. This cofactor was developed by Dr. Takumi Okuda; it was inspired by the ubiquitous natural cofactor SAM (S-adenosylmethionine). This is also where the name of the new ribozyme comes from: SAMURI stands for “SAM-analogue utilising ribozyme.”
A circadian-like gene network programs the timing and dosage of heterochronic miRNA transcription during C. elegans development
by Brian Kinney, Shubham Sahu, Natalia Stec, Kelly Hills-Muckey, Dexter W. Adams, Jing Wang, Matt Jaremko, Leemor Joshua-Tor, Wolfgang Keil, Christopher M. Hammell in Developmental Cell
There’s a rhythm to developing life. Growing from a tiny cell cluster into an adult organism takes precise timing and control. The right genes must turn on at the right time, for the right duration, and in the correct order. Losing the rhythm can lead to diseases like cancer. So, what keeps every gene on beat?
Cold Spring Harbor Laboratory (CSHL) Professor Christopher Hammell has found that in the worm C. elegans, this genetic orchestra has no single conductor. Instead, a quartet of molecules works in concert to time each developmental stage. Hammell says this process shares some similarities with the circadian clocks that control human behavior. Understanding how the worm’s clock is regulated could help explain how time affects development in other animals.
Hammell explains: “This clock we’ve discovered sets the cadence of development. It’s a coordinator of the orchestra. It controls when the trombone goes, how loud it gets, and how long the note lasts.”
Each stage of C. elegans’ development begins with two proteins, NHR-85 and NHR-23. They work together to spark a pulse of gene expression, switching on the microRNA lin-4, which controls stem cell development patterns. The pulse’s timing, strength, and duration depend on the short stretch when NHR-85 and NHR-23 interact, and another protein, LIN-42, which ends each developmental period by shutting off NHR-85.
“Mess up the orchestra — it’ll still make sound,” Hammell says. “But the way the music changes lets us know proper timing is critical for development.”
Hammell teamed with Wolfgang Keil from Paris’ Curie Institute to observe this gene expression cycle in action. C. elegans takes about 50 hours to reach adulthood. During that time, it’s always on the move, like a restless teenager. The team developed a new imaging technique to hold the tiny worm in place long enough to take pictures and video. This let them measure each developmental beat as it occurred.
“We could see every time genes turned on from birth to adulthood,” Hammell says. “This kind of imaging had never been done in animals, only in single cells.”
Hammell is now working with CSHL Professor & HHMI Investigator Leemor Joshua-Tor to image how clock proteins interact over time.
“We want to work out, with even more precision, how this clock operates,” Hammell says. “Humans can do things like write music or perform calculus, not because we have a calculus or music gene, but because our developmental clocks enable our brain to develop longer into a more complex organ.”
Airborne transmission of human-isolated avian H3N8 influenza virus between ferrets
by Honglei Sun, Han Li, Qi Tong, Qiqi Han, Jiyu Liu, Haili Yu, Hao Song, et al in Cell
A new study from researchers in China and Nottingham has discovered that a subtype of avian flu virus, endemic in poultry farms in China, is undergoing mutational changes, which could increase the risk of the disease being passed on to humans.
Researchers also say that the findings raise concerns of a potential epidemic or pandemic in the making and that concerted research is necessary to closely monitor such viruses in poultry and humans.
The results report on the characterisation of a human isolate — from a human patient — of the H3N8 avian influenza virus (AIV). Using laboratory mice and ferrets as models for human infection, the study found that virus has undergone several adaptive changes to cause severe animal infections and making it transmissible by the airborne route between animals.
In humans, the avian H3N8 virus infection has been found to cause acute respiratory distress syndrome and can even be fatal. The virus is widespread in chicken flocks; however previously, the features of how it might be transmitted from animals to humans is poorly understood.
“We demonstrate that an avian H3N8 virus isolated from a patient with severe pneumonia replicated efficiently in human bronchial and lung epithelial cells, was extremely harmful in its effects in laboratory mammalian hosts and could be passed on through respiratory droplets,” says Professor Kin-Chow Chang,at the University of Nottingham.
“Importantly, we discovered that the virus had acquired human receptor binding preference and amino acid substitution PB2-E627K, which are necessary for airborne transmission. Human populations, even when vaccinated against human H3N2 virus, appear immunologically naïve to emerging mammalian adapted H3N8 AIVs and could be vulnerable to infection at epidemic or pandemic proportion.
“Acid resistance of influenza virus is also an important barrier for avian influenza virus to overcome to acquire the adaptability and transmissibility in new mammals or humans. The current novel H3N8 virus has not acquired the acid resistance yet. So, we should pay attention to the change on acid resistance of the novel H3N8 virus.”
MISC
Subscribe to Paradigm!
Medium. Twitter. Telegram. Telegram Chat. Reddit. LinkedIn.
Main Sources
Research articles
