Tag Archives: #gene

Internal Clocks Drive Beta Cell Regeneration (Medicine)

Scientists from UNIGE and HUG identify the essential role of circadian clocks in the regeneration of insulin-producing cells.

Certain parts of our body, such as the skin or liver, can repair themselves after a damage. Known as cell regeneration, this phenomenon describes how cells that are still functional start to proliferate to compensate for the loss. For the past 30 years, scientists have been investigating the regenerative potential of beta cells, pancreatic cells in charge of the production of insulin. Beta-cell population is indeed partially destroyed when diabetes occurs, and regenerating these cells represents an outstanding clinical challenge. By studying diabetic mice, scientists from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG, observed that this regeneration mechanism was under the influence of circadian rhythms – the molecular clocks regulating metabolic functions according to a 24-hour cycle of alternating day-night. In addition, the scientists identified the essential role of the core clock component BMAL1 in this process. These results, to be read in the journal Gene and Development, allow new perspectives to be envisaged to promote beta cell regeneration.

Image of pancreatic islets showing proliferation markers (in red staining) in the nuclei (in blue) of insulin-producing-cells (in green). © UNIGE/Dibner

Compensatory proliferation, in which cells begin to actively divide to replace those that have been damaged, is a biological mechanism that is both well-known and poorly understood. «And this is particularly true for pancreatic beta cells, whose regenerative mechanism stays largely unexplored despite decades of research,» explains Dr Charna Dibner, head of the Circadian Endocrinology Laboratory at UNIGE Faculty of Medicine’s the Departments of Medicine and Cell Physiology and Metabolism, as well as at the Diabetes Centre, and at the HUG. «However, deciphering this phenomenon and above all finding out how to promote it could be a game changer for controlling diabetes.»

Day-night rotation is essential

To explore the connection between internal biological clocks and beta cell regeneration, Charna Dibner’s team first observed two groups of mice with only 20% beta cells remaining after targeted massive ablation. Mice in a first group were arrhythmic, whereas the control group had perfectly functional clocks. «The result was very clear: the mice bearing dysfunctional clocks were unable to regenerate their beta cells, and suffered from severe diabetes, while the control group animals had their beta cells regenerated; in just a few weeks, their diabetes was under control,» says Volodymyr Petrenko, a researcher in Dr. Dibner’s laboratory and the leading scientist in this study. By measuring the number of dividing beta cells across 24 hours, the scientists also noted that regeneration is significantly greater at night, when the mice are active.

The BMAL1 gene, metronome of cell activity

The arrhythmic mice were lacking the BMAL1 gene, which codes for the protein of the same name, a transcription factor known for its key action in the functioning of circadian clock. «Our analyses show that the BMAL1 gene is essential for the regeneration of beta cells,» adds Volodymyr Petrenko. In addition, large-scale transcriptomic analyses over a 24-hour period, conducted in collaboration with Prof. Bart Vandereycken at the Mathematics Department of the UNIGE, revealed that the genes responsible for regulating cell cycle and proliferation were not only upregulated, but also acquired circadian rhythmicity. “BMAL1 seems to be indeed central for our investigation,” stresses Charna Dibner. “However, whether the regeneration requires functional circadian clocks themselves, or only BMAL1, whose range of functions goes beyond clocks remains unclear. That is what we would like to find out at present.” The scientists also want to explore the function of alpha cells, which produce glucagon, the hormone that antagonises insulin, in this model. The arrhythmic mice indeed showed very high levels of glucagon in the blood. “A detailed understanding of these mechanisms must now be pursued, in an attempt to explore the possibility of triggering beta cell regeneration in humans in the future” conclude the authors.

References: https://doi.org/10.1101/gad.343137.120%20

Provided by University of Geneve

Study Discovers Gene That Helps Us Know When It’s Time To Urinate (Biology)

Results suggest ‘sixth sense’ PIEZO2 gene may help body sense a full urinary bladder.

In a National Institutes of Health (NIH)-funded study involving both mice and patients who are part of an NIH Clinical Center trial, researchers discovered that a gene, called PIEZO2, may be responsible for the powerful urge to urinate that we normally feel several times a day. The results, published in Nature, suggest that the gene helps at least two different types of cells in the body sense when our bladders are full and need to be emptied. These results also expand the growing list of newly discovered senses under the gene’s control.

NIH funded researchers discovered that a gene called PIEZO2 may help us sense when our bladders are full, and it is time to urinate. Above is an example of a mouse bladder used in the study. ©Courtesy of Patapoutian lab, Scripps Researcher Institute, La Jolla, CA.

“Urination is essential for our health. It’s one of the primary ways our bodies dispose of waste. We show how specific genes and cells may play critical roles in initiating this process,” said Ardem Patapoutian, Ph.D., professor, Scripps Research Institute, La Jolla, CA and a senior author of the paper. “We hope that these results provide a more detailed understanding of how urination works under healthy and disease conditions.”

Urine is produced when the kidneys extract waste and excess water from the blood and send it to the bladder. Over time, it fills up and expands like a balloon, putting tension on the bladder muscles. Then, at a certain point, the body senses that it is reaching a limit, which triggers the urge to urinate.

The PIEZO2 gene contains instructions for making proteins that are activated when cells are stretched or squeezed. In this study, the researchers found that patients who are born with a genetic deficiency in PIEZO2 have trouble sensing bladder filling while experiments in mice suggested the gene plays two critical roles in this process. It may help certain bladder cells gauge expansion while also sparking neurons to relay tension signals to the rest of the nervous system.

The study was a collaboration between Dr. Patapoutian’s team and researchers working in NIH labs led by Alex Chesler, Ph.D., senior investigator, at the NIH’s National Center for Complementary and Integrative Health (NCCIH) and a senior author of the paper, and Carsten Bönnemann, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

In 2010, Dr. Patapoutian’s team discovered the PIEZO2 gene along with a similar gene called PIEZO1 in a line of mouse brain tumors. Before then, scientists knew of only a few rare examples from flies, worms, and mice in which a gene helped tissue, such as hairy skin cells, sense changes in shape and pressure. Since the discovery, Dr. Patapoutian’s team and others have primarily shown in mice that the PIEZO2 gene may play many roles throughout the body including controlling the sense of touch, vibration, pain, and proprioception, the unconscious awareness of one’s body in space.

NIH funded researchers showed how the PIEZO2 gene may help dorsal root ganglion neurons relay full bladder signals to the brain. Above is a picture of mouse DRGs colored purple. The PIEZO2 gene is colored light blue. ©Courtesy of Patapoutian lab, Scripps Researcher Institute, La Jolla, CA.

More recently Dr. Patapoutian’s and Dr. Chesler’s teams had been exploring whether PIEZO2 played a role in urination.

“There were a lot of reasons to think that PIEZO2 could be important for urination. Theoretically, it made sense as it is a pressure sensor for other internal sensory processes,” said Kara L. Marshall, Ph.D., a post-doctoral fellow on Dr. Patapoutian’s team and the lead author of the study.

Then in 2015, a breakthrough happened. The NIH researchers discovered people who were born with disabling mutations in their PIEZO2 genes. Initial evaluations of these PIEZO2 deficient individuals at the NIH’s Clinical Center reproduced some of the mouse results. They had no sense of proprioception and could not feel some forms of touch and pain. They also had something else in common.

“We were really struck by what we heard during background interviews with patients and their families. Almost everyone mentioned that the patients had problems with urination. As children, they had trouble potty training. They would often have urinary tract infections. And most of them follow a daily urination schedule,” said Dimah Saade, M.D., a clinical fellow on Dr. Bönnemann’s team and an author of the paper. “After seeing a consistent pattern, we decided to take a closer look.”

The researchers examined medical records, performed ultrasound scans, administered questionnaires, and conducted detailed interviews with 12 patients, 5 to 43 years of age, and their families.

Nearly all the patients claimed they could go an entire day without feeling the need to urinate and most urinated less than the normal five to six times per day. In fact, three patients reported only going once or twice a day. Five patients reported that when they finally do feel a need, it comes on as an abrupt urge. Seven patients reported that the act of urinating was difficult. They either had to wait for it to happen or needed to press their lower abdomen for it to start.

“These results strongly suggested that PIEZO2 plays a role in urination,” said Dr. Marshall. “We wanted to know how it may do this.”

In-depth experiments in mice helped them address this question.

Initially, the researchers found that the PIEZO2 gene was highly active in a few dorsal root ganglion (DRG) neurons that send nerve signals from the mouse bladder to the brain. Aided by an advanced, real-time imaging system, they saw that the cells lit up with activity when a mouse’s bladder filled with fluid. They also found that the PIEZO2 gene was turned on in some “umbrella” cells which are found among the cells that line the inside of a bladder.

“These were the first clues to understanding where in the urinary tract PIEZO2 worked. They suggested that it may help control the bladder,” said Nima Ghitani, Ph.D., a post-doctoral fellow in Dr. Chesler’s lab and an author of the study.

Next, they found that deleting the gene from the neurons and umbrella cells not only reduced the cells’ responses to bladder filling but also caused the mice to have problems with urination. The mutant mice showed some signs of incontinence and urinated randomly in their cages instead of in a corner as seen with control mice. Meanwhile, mutant mouse bladders required more fluid and greater pressure than normal to trigger urination which was reminiscent of the patient reports.

They also found that deleting the gene from the two cell types had longer lasting effects. For instance, the muscles of the mutant bladders were thicker than controls, suggesting the loss of sensation remodeled the bladder.

“Neurologists have always known that there’s a strong link between the nervous system and bladder control, both on a conscious as well as on an automatic level,” said Dr. Bönnemann. “Our patients together with the results in the mouse models teach us how the loss of the critical sensor PIEZO2 profoundly disrupts the wiring behind normal bladder control, ultimately reshaping the bladder itself.”

Finally, the researchers found that deleting the PIEZO2 gene from either the umbrella cells or the DRG neurons produced similar results as deleting it from both cell types simultaneously. Eliminating the gene from either cell lengthened the time that mice would take before feeling the need to squeeze their bladders and it increased the pressure applied during each squeeze.

“Our results show how the PIEZO2 gene tightly coordinates urination,” said Dr. Chesler. “This is a major advance in our understanding of interoception – or the sense of what’s going inside our bodies.”

In the future, the researchers will continue to examine the role PIEZO2 plays in urination and other interoceptive senses while also exploring the clinical implications of their discovery for the millions suffering from urinatory control problems.

References: Marshall, K.L., Saade, D., Ghitani N et al., PIEZO2 in sensory neurons and urothelial cells coordinate urination in humans and in mice. Nature, October 14, 2020
DOI: 10.1038/s41586-020-2830-7. http://dx.doi.org/10.1038/s41586-020-2830-7

Provided by National Center for Complementary and Integrative Health (NCCIH)

There’s No Single Gene For left-handedness: At Least 41 Regions Of DNA Are Involved (Biology)

Most people consistently use the same hand to do tasks that require skill and control such as writing or threading a needle. We know genetics plays a big part in which hand a person prefers, but it has been difficult to identify the exact genes responsible.

To find out more, researchers from University Of Queensland analysed the DNA of more than 1.7 million people and discovered 41 regions of the genome associated with being left handed and another seven associated with being ambidextrous.

What makes people left-handed?

About 88% of people prefer to use their right hand for complex tasks, around 10% prefer their left hand, and the other 2% report they do not have a preference and can use either hand. Hand preference develops so early that it can be seen in the womb.

Handedness tends to stabilise around the time children are learning to draw. In the absence of injury or training it remains constant throughout life. Evidence from historic human populations suggests it has been this way for hundreds of thousands of years.

Research examining patterns of handedness in twins and families shows most of the variation is down to non-genetic factors, such as training and the environment in which they gain early motor skills. However, genetics does play a significant role.

There is no single gene for handedness

Since the mid-1980s more than 100 journal articles have explored the idea that a single gene might influence handedness. These theories suggested one variant of the gene would bias an individual towards right-handedness, while the alternate variant led to handedness being randomly determined.

While there have been many theories attempting to explain different human characteristics via single genes, in recent years researchers of University of Queensland have discovered that the reality is often much more complicated. More recent research uses genome-wide association studies (GWAS) to look for a relationship between a trait of interest and the number of copies of a genetic variant someone has. These analyses are run for millions of variants located across the genome.

These genome-wide studies have shown that almost all human traits are influenced by many hundreds or thousands of genetic variants. Often these variants are located between genes whose purpose is not clearly identifiable, in what used to be called “junk DNA”.

GWAS has also shown most traits are influenced by large numbers of genes which each contribute a very small effect, rather than a single gene which has a large effect. To track these small effects, large collaborative studies with many participants are required in order to identify the individual genetic variants involved.

What GWAS reveals about handedness?

In 2009 researchers started a project involving researchers from around the world to hunt for genetic variants that influence handedness using GWAS. They did not recruit participants based on their handedness, so the number of left-handed people was relatively small. As a result, they have only recently gathered enough to undertake robust analyses.

Their study brought together analyses of data from 1,766,671 people. Of these people, 194,198 were left-handed and 37,637 were ambidextrous. They found 41 regions of the genome associated with left-handedness and seven regions associated with ambidexterity.

Many of the regions of the genome associated with left-handedness contained genes that code for microtubule proteins. These proteins play important roles during development in the migration of neurons and in the ability of the brain to adapt to changes in the environment.

Interestingly, genes that influence other asymmetries in the body, such as which side of the body the heart is located on, were not associated with handedness in our study.

Another important finding was that there was little overlap between the regions of the genome associated with left-handedness and those associated with ambidexterity. This suggests that ambidexterity is more complicated than they previously thought. The mechanisms that influence the direction of hand preference might be different from those that influence the degree of hand preference.

These findings give researchers promising new leads but more work is needed to identify further genetic variants that influence handedness. There is also a long way to go before we understand how these variants play a role in someone becoming right-handed, left-handed or ambidextrous.

References: Cuellar-Partida, G., Tung, J.Y., Eriksson, N. et al. Genome-wide association study identifies 48 common genetic variants associated with handedness. Nat Hum Behav (2020). https://doi.org/10.1038/s41562-020-00956-y link: https://www.nature.com/articles/s41562-020-00956-y

Provided by University Of Queensland

Penn Medicine Researchers Discover A Rare Genetic Form Of Dementia (Medicine)

A new, rare genetic form of dementia has been discovered by a team of Penn Medicine researchers. This discovery also sheds light on a new pathway that leads to protein build up in the brain — which causes this newly discovered disease, as well as related neurodegenerative diseases like Alzheimer’s Disease — that could be targeted for new therapies. The study was published today in Science.

Abnormal neurofibrillary tangles (NFTs) — a buildup of tau protein in parts of the brain — helped Edward Lee, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, and other Penn Medicine scientists uncover this new form of dementia. ©Edward Lee

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a buildup of proteins, called tau proteins, in certain parts of the brain. Following an examination of human brain tissue samples from a deceased donor with an unknown neurodegenerative disease, researchers discovered a novel mutation in the Valosin-containing protein (VCP) gene in the brain, a buildup of tau proteins in areas that were degenerating, and neurons with empty holes in them, called vacuoles. The team named the newly discovered disease Vacuolar Tauopathy (VT)–a neurodegenerative disease now characterized by the accumulation of neuronal vacuoles and tau protein aggregates.

“Within a cell, you have proteins coming together, and you need a process to also be able to pull them apart, because otherwise everything kind of gets gummed up and doesn’t work. VCP is often involved in those cases where it finds proteins in an aggregate and pulls them apart,” Edward Lee, MD, PhD, an assistant professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. “We think that the mutation impairs the proteins’ normal ability to break aggregates apart.”

The researchers noted that the tau protein they observed building up looked very similar to the tau protein aggregates seen in Alzheimer’s disease. With these similarities, they aimed to uncover how this VCP mutation is causing this new disease — to aid in finding treatments for this disease and others. Rare genetic causes of diseases can very often offer insight into more prevalent ones.

The researchers first examined the proteins themselves, in addition to studying cells and an animal model, and found that the tau protein buildup is, in fact, due to the VCP mutation.

“What we found in this study is a pattern we’ve never seen before, together with a mutation that’s never been described before,” Lee said. “Given that this mutation inhibits VCP activity, that suggest the converse might be true — that if you’re able to boost VCP activity, that could help break up the protein aggregates. And if that’s true, we may be able to break up tau aggregates not only for this extremely rare disease, but for Alzheimer’s disease and other diseases associated with tau protein aggregation.”

These findings describe a new biologic function of VCP, define a new mechanism that leads to tau protein aggregation, and suggest a new possible therapeutic target for the treatment of AD.

References: Nabil F. Darwich, Jessica M. Phan, Boram Kim, “Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau”, Science, Oct 2020: eaay8826 DOI: 10.1126/science.aay8826 link: https://science.sciencemag.org/content/early/2020/09/30/science.aay8826

Provided by University of Pennsylvania school Of Medicine

Mosquitos Lost An Essential Gene With No Ill Effects (Entomology / Biology)

University of Maryland entomologists discovered that a gene critical for survival in other insects is missing in mosquitos–the gene responsible for properly arranging the insects’ segmented bodies. The researchers also found that a related gene evolved to take over the missing gene’s job. Although laboratory studies have shown that similar genes can be engineered to substitute for one another, this is the first time that scientists identified a gene that naturally evolved to perform the same critical function as a related gene long after the two genes diverged down different evolutionary paths.

This image shows the exoskeletons of a normal mosquito larva on the left and a mosquito larva with the gooseberry gene edited out on the right. Image credit: Alys Jarvela/University of Maryland.

The work emphasizes the importance of caution in genetic studies that use model animals to make conclusions across different species. It also points to a new potential avenue for research into highly targeted mosquito control strategies. The research study was published in the September 30, 2020, issue of the journal Communications Biology.

“Every single arthropod has a segmented body plan. And you would think it develops the same way in all of them. But what we found is that it doesn’t,” said Alys Jarvela, a postdoctoral associate in the UMD Department of Entomology and the lead author of the study. “We learn a lot in biology by studying a process in a model organism and assuming that it works essentially the same way, using the same genes, in other organisms. That is still an incredibly useful approach. But, now we know that there is also a possibility for gene substitutions to be made in nature.”

Jarvela discovered the missing gene in mosquitos by accident. She was studying crickets and attempting to cross-check her genetic samples by comparing the gene sequences of crickets with those of other insects. She was specifically interested in a gene called paired, one of a handful of genes that guides the pattern of repeated parts in segmented animals like insects. Laboratory studies had shown that when paired is knocked out or silenced in fruit flies, every other segment of the insect’s body fails to develop, and it doesn’t survive.

“I was just trying to find the mosquito version of paired to use as a reference point, and I couldn’t find, it,” Jarvela said.

When she searched for paired in all publicly available databases of mosquito genomes, she discovered it was missing from every mosquito species represented. “Once we accepted that the gene was really absent, we thought that was a pretty wild mystery and immediately changed gears to satisfy our curiosity,” Jarvela said.

Jarvela’s team searched the genomes of fly species closely related to mosquitos and found they all contained the paired gene. This indicated that the loss of paired is a recent evolutionary event that took place only in mosquitos. It was clear to the researchers that some other gene in mosquitos must be performing the same function as paired does in other insects.

They found clues suggesting which gene could be involved in a 1996 experiment on fruit flies. In that study, scientists knocked out paired and replaced it with a closely related gene called gooseberry, which normally has a distinct role at a later time in development. That was a highly engineered experiment, but it showed that when gooseberry was manipulated to express at the right time during development, fruit flies without the paired gene developed normal alternating segments and survived.

To find out if gooseberry had naturally evolved as a substitute for paired in mosquitos, Jarvela and her team used CRISPR to edit gooseberry out of a mosquito species called Anopheles stephensi. The mutated mosquito embryos looked like laboratory fruit fly embryos that had paired knocked out.

“This work shows that even when different species share a trait or feature, the genetic mechanisms underlying this shared trait may be different,” said Leslie Pick, professor and chair of the Department of Entomology at UMD and the study’s senior author. “In the case reported in this paper, segmentation still happens even though a gene we thought was essential is lost. Our next steps will be to search for additional examples of variation in gene regulatory networks in insects and try to determine how genetic rewiring occurs in nature.”

Jarvela is also interested in probing other aspects of mosquito development that may be affected by the loss of the paired gene. In addition to controlling segmentation, which is critical for survival, paired influences male fertility in fruit flies.

“That means different genes probably regulate male fertility in mosquitos, and they might be unique to the mosquito, which could potentially provide a powerful avenue for controlling mosquitoes without harming other insects such as butterflies and bees,” Jarvela said.

References: Cheatle Jarvela, A.M., Trelstad, C.S. & Pick, L. Regulatory gene function handoff allows essential gene loss in mosquitoes. Commun Biol 3, 540 (2020). https://doi.org/10.1038/s42003-020-01203-w link: https://www.nature.com/articles/s42003-020-01203-w

Provided by University Of Maryland