Category: Genetics

Categories : Gender GeneticsTags :

Study Finds Testosterone’s Importance for Success Overrated

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Ball-and-stick model of the testosterone molecule, C19H28O2, as found in the crystal structure of testosterone monohydrate. Credit: Ben Mills, Wikimedia Commons.

With the Olympics underway, testosterone is again in the spotlight over its role in enhancing physical performance, with rules about its natural level being once again debated. It has also been popularly thought to be involved in success in other endeavours – but its importance in this regard may be overrated.

New research has found little evidence that testosterone exerts a meaningful influence on successes in life for men or women. The study in fact suggests that testosterone’s importance outside of physical endeavours could be even less important than previously believed.

In men, it is known that testosterone is linked to socioeconomic position, such as income or educational qualifications.  Researchers from the University of Bristol’s Population Health Sciences (PHS) and MRC Integrated Epidemiology Unit (IEU) set out to determine whether this is because testosterone has an influence on socioeconomic position, as opposed to socioeconomic circumstances affecting testosterone levels, or if it was a case of health affecting both. The findings are published in Science Advances.

To isolate effects of testosterone itself, the investigators used Mendelian randomisation in a sample of 306,248 UK adults from UK Biobank. They explored testosterone’s influence on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and BMI, and on risk-taking behaviour.  

Dr Amanda Hughes, Senior Research Associate in Epidemiology in Bristol Medical School: Population Health Sciences (PHS), said: “There’s a widespread belief that a person’s testosterone can affect where they end up in life. Our results suggest that, despite a lot of mythology surrounding testosterone, its social implications may have been over-stated.”

First, the team identified genetic variants linked to higher testosterone levels, and explored their links to outcomes. Since genetic variations are essentially fixed throughout a lifetime, it is highly unlikely that they are affected by socioeconomic circumstances, health, or other environmental factors.

In common with prior studies, multivariate analysis showed men with higher testosterone had higher household income, lived in less deprived areas, and were more likely to have a university degree and a skilled job. Higher testosterone in women was linked to lower socioeconomic position, including lower household income, living in a more deprived area, and lower chance of having a university degree. Consistent with previous evidence, higher testosterone was associated with better health for men and poorer health for women, and greater risk-taking behaviour for men.

In contrast, the Mendelian randomisation method showed there was little evidence that the testosterone-linked genetic variants were associated with any outcome for men or women. The research team concluded that there is little evidence that testosterone meaningfully affected socioeconomic position, health, or risk-taking in men or women. The study suggests that – despite the mythology surrounding testosterone – its importance is much less than previously held.

Since the results for women were less precise than the men’s, the influence of testosterone in women could be further explored with larger sample sizes.  

Dr Hughes added: “Higher testosterone in men has previously been linked to various kinds of social success. A study of male executives found that testosterone was higher for those who had more subordinates. A study of male financial traders found that higher testosterone correlated with greater daily profits. Other studies have reported that testosterone is higher for more highly educated men, and among self-employed men, suggesting a link with entrepreneurship.

“Such research has supported the widespread idea that testosterone can influence success by affecting behaviour. There is evidence from experiments that testosterone can make a person more assertive or more likely to take risks – traits which can be rewarded in the labor market, for instance during wage negotiations. But there are other explanations. For example, a link between higher testosterone and success might simply reflect an influence of good health on both. Alternatively, socioeconomic circumstances could affect testosterone levels. A person’s perception of their own success could influence testosterone: in studies of sports matches, testosterone has been found to rise in the winner compared to the loser.”

Source: University of Bristol

Journal information: Testosterone and socioeconomic position: Mendelian Randomization in 306,248 men and women in UK Biobank’, Science Advances (2021).

Categories : GeneticsTags :

Mice Born From Stem Cell-derived Gametes

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Photo by Kanashi on Unsplash
Photo by Kanashi on Unsplash

For the first time, mice have been born from gametes that have been created entirely from stem cells, marking the beginning of a revolutionary new reproductive option.

The experiment is the brainchild of Dr Katsuhiko Hayashi of Kyushu University, who has led the pursuit of making gametes outside of a living body. If adapted for humans, these wild reproductive pursuits are bound to shake up our entire conception of the beginning of life, similar to the way “test-tube” babies did when in vitro fertilisation (IVF) was first introduced.

Dr Hayashi dreams of even bigger possibilities; since stem cells can be rapidly created from skin or other cells, they are an endless source of raw material to make sperm and egg cells. These gametes, if fully functional, can merge into a zygote inside a test tube, be transplanted into a surrogate, and birth a new generation without ever seeing testes or ovaries.

Though still far off for humans, in vitro gametogenesis, or IVG, has great potential. Researchers can use these lab-grown models to better understand how reproductive cells form and mature. For couples struggling to conceive, or people who’ve lost reproductive function due to diseases like cancer, IVG would offer a new route towards pregnancy. Same-sex couples could also potentially conceive children with their own genetic makeup. There are many possibilities, and a wide range of ethical problems.

The basis of the technology uses induced pluripotent stem cells (iPSCs), which can be nudged in any direction, including sperm and egg. Back in 2011, Dr Hayashi showed that by bathing stem cells in a particular chemical soup, his team was able to produce sperm cell precursors, with the capacity to turn into functional sperm.

In 2016, the team achieved the same with eggs in mice, mimicking the entire process of how ovaries make eggs – which were used to produce healthy pups. However, eggs made in a test tube couldn’t develop naturally outside the ovary. Fresh ovarian tissue from mice was needed, creating an obvious challenge for fertility treatments in humans.

In the current study, the team focused on the support cells that normally encapsulate a developing egg. These support cells thrive inside the ovary, secreting hormones and nutrients that help support the metabolic needs of an egg  – a crucial step, which includes forming ovarian follicles for the eggs to mature in.

These ovary-supporting cells can also be made from stem cells if the right chemical keys are used, and so after five years Dr Hayashi figured out those keys. Many of them sport fanciful names like ‘sonic hedgehog‘ (SHH), but most of these proteins belong to the morphogen family, in that they can morph the physical structure and identity of a tissue.

After dousing stem cells with this soup, the cells differentiated into foetal ovary supporting cells, with a gene expression profile closely mimicking that of their natural counterparts.

Next, the researchers added precursor immature egg cells, also made from stem cells. Together, the cells coalesced into tiny ovarian follicles, with support cells forming a bubble wrapping the developing egg. The eggs were then fertilised with sperm, transplanted into surrogate mouse mothers, and after normal pregnancies, resulted in about a dozen healthy pups. Those mice eventually gave birth to babies of their own.

The artificial ovary produces mature eggs less effectively than its natural counterpart, suggesting there’s still much to be learned about this stage of reproduction.

Application of this technology to assisted reproduction in humans is still decades away: human reproductive cells take far longer to mature than those in mice, and likely require different supporting nutrients for the sperm, egg, and surrounding tissue.

The team is now testing their chemical soup in marmosets, to be followed by primates.

Currently no laws or ethical frameworks deal with IVG, since the technology is so new.

Dr Hayashi is taking it step by step, and welcoming public discourse before even considering any clinical use. The first step, he said, is verifying the quality of the stem-cell derived eggs, adding, “That could take a long, long time.”

Source: SingularityHub

Categories : Cancer GeneticsTags :

Comprehensive Genome Sequencing Can Improve Cancer Outcomes

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Image source: National Cancer Institute

Researchers from St Jude Children’s Research Hospital have demonstrated the feasibility of comprehensive genomic sequencing for all paediatric cancer patients, which maximises the lifesaving potential of precision medicine.

All 309 patients who enrolled in the study were offered whole genome and whole exome sequencing of germline DNA. For the 253 patients for whom adequate tumour samples were available, whole genome, whole exome and RNA sequencing of tumour DNA was carried out.

Overall, 86% of patients had at least one clinically significant variation in tumour or germline DNA. Those included variants related to diagnosis, prognosis, therapy or cancer predisposition. An estimated 1 in 5 patients had clinically relevant mutations that would not have been picked up with standard sequencing methods.

“Some of the most clinically relevant findings were only possible because the study combined whole genome sequencing with whole exome and RNA sequencing,” said Jinghui Zhang, PhD, St Jude Department of Computational Biology chair and co-corresponding author of the study.

While such comprehensive clinical sequencing is not widely available, as the technology becomes less expensive and accessible to more patients, comprehensive sequencing will become an important addition to paediatric cancer care.

“We want to change the thinking in the field,” said David Wheeler, PhD, St Jude Precision Genomics team director and a co-author of the study. “We showed the potential to use genomic data at the patient level. Even in common pediatric cancers, every tumor is unique, every patient is unique.

“This study showed the feasibility of identifying tumour vulnerabilities and learning to exploit them to improve patient care,” he said.

Tumour sequencing resulted in a change in treatment for 12 of the 78 study patients for whom standard of care was unsuccessful. In four of the 12 patients, the treatment changes stabilised disease and extended patient lives. Another patient, one with acute myeloid leukaemia, went into remission and was cured by blood stem cell transplantation.

“Through the comprehensive genomic testing in this study, we were able to clearly identify tumor variations that could be treated with targeted agents, opening doors for how oncologists manage their patients,” said co-corresponding author Kim Nichols, MD, St Jude Cancer Predisposition Division director.

The results of the study were published online in the journal Cancer Discovery.

Source: St. Jude Children’s Research Hospital

Journal information: Newman, S., et al (2021) Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discovery. doi.org/10.1158/2159-8290.CD-20-1631.

Categories : Ageing GeneticsTags :

Junk DNA Yields Insights into Ageing and Cancer

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Findings from a new study into ‘junk DNA’ have brought scientists one step closer to solving the mysteries of ageing and cancer.

Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, led a team which recently identified a DNA region known as VNTR2-1 which seems to drive activity of the telomerase gene, which has been shown to prevent ageing in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).

The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells and which shorten over time until cells are no longer able to divide.

However, in certain cell types, such as reproductive cells and cancer cells, the telomerase gene’s activity ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.

Understanding how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Prof Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.

Zhu said that VNTR2-1’s discovery is especially noteworthy due to the type of DNA sequence it represents.

“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” noted Prof Zhu. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matter in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”

In previous work, deleting the DNA sequence from human and mouse cancer cells caused telomeres to shorten, cells to age, and tumours to stop growing. They conducted a subsequent study measuring the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats of the DNA to as long as 160 repeats.

“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Prof Zhu said.

Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Prof Zhu said that a shorter sequence does not necessarily translate to a shorter lifespan, since the telomerase gene is less active with possibly a shorter telomere length which could reduce cancer risk.

“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Prof Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”

Prof Zhu observed that many African Americans in the United States for generations have Caucasian ancestry, which could have added this sequence. So he and his team hope to next be able to study the sequence in an African population.

Source: Washington State University

Journal information: Xu, T., et al. (2021) Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene. PNAS. doi.org/10.1073/pnas.2019043118.

Categories : GeneticsTags :

Misattributed Paternity Decreasing – In Sweden, At Least

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Photo by Drew Hays on Unsplash

The frequency of misattributed paternity, where the assumed father is not the biological father, is low and decreasing in Sweden, according to an analysis of nearly 2 million family units with children born mainly between 1950 and 1990.

The rates of misattributed paternity are estimated to range from 0.8% to 30% across different countries and studies. Taking information from genetic and behavioural studies, the article characterised that individuals at higher risk being those who conceive younger, live in deprived circumstances, are in long term relationships (rather than marriages), or in certain cultural groups.

In the study published in the Journal of Internal Medicine, the overall rate of misattributed paternity was 1.7%, with rates closer to 1% in more recent decades.

The researchers used nationwide ABO blood group data and a nationwide register of familial relationships in Sweden. These data were analysed using both a frequentist Poisson model and the Bayesian Gibbs model. The study, which drew on 1.95 million mother-father-offspring family units estimated that the frequency of misattributed paternity was 1.7% in both models. Misattributed paternity was more common among parents with low educational levels, and has decreased over time to a current 1%.

The researchers noted that beyond its general scientific and societal relevance, the frequency of misattributed paternity has an effect on studies on hereditary conditions. Fortunately, the study’s findings indicate that misattributed paternity is unlikely to have large effects on such studies.
“Using simple but elegant methods, together with large-scale register data, we present population-based estimates of a peculiar question. These findings should once and for all put an end to the common misconception of overinflated occurrences of misattributed paternity in the general population,” said lead author Torsten Dahlén, of the Karolinska Institutet, in Sweden.

Source: EurekAlert!

Categories : GeneticsTags :

World First in Vivo CRISPR Gene Editing Treatment

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Image by liyuanalison from Pixabay

An intravenous CRISPR gene editing infusion lowered levels of a disease-causing protein in vivo for the first time in humans, according to interim findings from a phase I trial.

Hereditary (ATTR) amyloidosis is a rare, rapidly progressive disease caused by a mutation in the  serum transthyretin (TTR) gene that results in the buildup of misfolded transthyretin and leads to the formation of amyloid deposits in the heart, gastrointestinal tract, and peripheral nerves. Life expectancy is about 3 to 15 years after the onset of neuropathy.
Researchers used the DNA-editing tool CRISPR-Cas9 to inactivate the TTR gene in liver cells to prevent misfolded TTR protein from being produced. The liver produces almost all circulating TTR.

The treatment reduced TTR by 87% in three people with hereditary transthyretin (ATTR) amyloidosis with polyneuropathy. The findings were published in the New England Journal of Medicine.

“This is the first successful demonstration of therapeutic gene editing within patients’ bodies, making it a watershed moment in modern medicine,” noted Kiran Musunuru, MD, PhD, MPH, director of the Genetic and Epigenetic Origins of Disease Program at the University of Pennsylvania in Philadelphia, who was not involved with the study.

“The investigators used lipid nanoparticle technology — the same technology used in COVID mRNA vaccines — to deliver CRISPR into the liver, with the goal of turning down a gene responsible for hereditary ATTR amyloidosis,” Dr Musunuru told MedPage Today.

“What was astonishing about this first-in-human study is not just that the treatment worked, but that it worked extremely well in patients, in one case turning off the disease gene close to 100%. It’s like launching a rocket ship in the hope of just getting into orbit, but making it all the way to the moon on the first try.”

Previously, other studies have removed blood stem cells from people with sickle cell anaemia and beta-thalassemia, editing them using CRISPR, and infusing them back into patients. In a trial of people with inherited blindness, a subretinal injection also has delivered CRISPR treatment.
Towever, the findings of NTLA-2001 represent the “first-ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR,” noted John Leonard, MD, president and CEO of Intellia Therapeutics, which co-sponsored the trial with Regeneron Pharmaceuticals.

“Solving the challenge of targeted delivery of CRISPR-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline,” said Dr Leonard in a statement.

NTLA-2001 is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system. It consists of a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.

The ongoing phase I study looked at safety and pharmacodynamic effects of single doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy. Half received 0.1 mg/kg, the other received 0.3 mg/kg.
Three patients had a p.T80A mutation, two a p.S97Y mutation, and one a p.H110D mutation. Three patients received no prior therapy; three previously had received diflunisal.

Dose-dependent reductions in serum TTR were seen from treatment with NTLA-2001. At day 28, mean serum TTR levels declined by 52% in the 0.1 mg/kg group and by 87% in the 0.3 mg/kg group. No serious adverse events were recorded.

Two treatments for hereditary ATTR amyloidosis nerve pain won FDA approval in 2018: patisiran (Onpattro), an RNA interference drug, and inotersen (Tegsedi), an RNA-targeting drug that reduces the production of TTR protein.

The NTLA-2001 study could have profound clinical implications, noted Joel Buxbaum, MD, of Scripps Research Institute in La Jolla, California, who was not involved with the study. “If, as the authors surmise, the effect is permanent, and without off-target effects when studied in a much larger patient population, it would be a significant improvement [over] current therapies for this class of disorders, at least with respect to frequency of therapy,” he said.

“However, all that depends on the clinical effect of long-term suppression of hepatic TTR synthesis,” Buxbaum told MedPage Today. “In the published studies of the various currently available ATTR therapeutics, approximately one-third of subjects have little or no clinical response, regardless of the degree of suppression of circulating protein levels, suggesting that while diminishing the supply side for TTR aggregation is likely to be necessary for clinical responsiveness, it may not be sufficient for optimal or profound therapeutic efficacy.”

After phase I studies are complete, the company plans to move forward to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis.

Source: MedPage Today

Journal information: Gillmore JD, et al “CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis” N Engl J Med 2021; DOI: 10.1056/NEJMoa2107454.

Categories : Cancer GeneticsTags :

Novel Approach Targets Pancreatic Cancers Which Depend on Mutant KRAS Gene

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KRAS Protein Structure. RAS is a family of related proteins that is expressed in all animals. KRAS is one of three RAS genes found in humans. RAS genes are mutated in approximately one-third of all human cancers. Photo by National Cancer Institute on Unsplash

Researchers have identified a novel drug that effectively thwarts pancreatic tumours that are addicted to the cancer-causing mutant KRAS gene.

Because early detection of pancreatic cancer is difficult, it has a low survival rate, accounting for just over 3% of all new cancer cases in the US, but leading to nearly 8% of all cancer deaths, according to the National Cancer Institute.

The KRAS gene was recognised more that 25 years ago as the component of Kirsten sarcoma virus responsible for oncogenesis. Since then, mutations of KRAS have been described in a large proportion of solid tumors ranging from more than 90% of pancreatic carcinomas to 20% to 30% of pulmonary adenocarcinomas.

Through a pre-clinical study, Said Sebti, PhD, associate director for basic research at VCU Massey Cancer Center, identified a novel drug that effectively thwarts pancreatic tumors that are addicted to the cancer-causing mutant KRAS gene. 

“We discovered a link between hyperactivation of the CDK protein and mutant KRAS addiction, and we exploited this link preclinically to counter mutant KRAS-driven pancreatic cancer, warranting clinical investigation in patients afflicted with this deadly disease,“ said Dr Sebti, who is also the Lacy Family Chair in Cancer Research at Massey and a professor of pharmacology and toxicology at the VCU School of Medicine. “Our findings are highly significant as they revealed a new avenue to combat an aggressive form of pancreatic cancer with very poor prognosis due mainly to its resistance to conventional therapies.”

In 90 percent of pancreatic cancers, KRAS is mutated. Prior studies have shown that some tumours harbouring mutant KRAS are in fact addicted to the mutant gene, meaning they cannot survive or grow without it. Sebti set out to discover if there is a drug that can specifically kill those tumours with a mutant KRAS addiction.

Searching for a suitable drug

Dr Sebti and colleagues used a three-pronged approach to tackle this question.

First of all, they mapped the blueprint of pancreatic cancer cells through global phosphoproteomics, showing them how the addicted and non-addicted tumours differ at the phosphoprotein level. They found two proteins, CDK1 and CDK2, which signalled which cells were addicted to mutant KRAS.

Additionally, they analysed a comprehensive database from the Broad Institute of MIT and Harvard which contains genome-wide CRISPR gRNA screening datasets. They discovered that CDK1 and CDK2 as well as CDK7 and CDK9 proteins were associated with mutant KRAS-addicted tumors.

Finally, they evaluated 294 FDA drugs to selectively kill mutant KRAS-addicted cancer cells over non-KRAS-addicted cancer cells in the lab. They determined the most effective drug in preclinical experiments was AT7519, an inhibitor of CDK1, CDK2, CDK7 and CDK9.

“Using three entirely different approaches, the same conclusion presented itself clearly to us: pancreatic cancer patients whose tumors are addicted to mutant KRAS could benefit greatly from treatment with the CDK inhibitor AT7519,” Dr Sebti said.

To further validate these findings in fresh tumours taken from pancreatic cancer patients the researchers found that AT7519 suppressed the growth of xenograft cells from five mutant KRAS pancreatic cancer patients who relapsed on chemotherapy and/or radiation therapies.

Though AT7519 had previously been tested unsuccessfully in a number of clinical trials, none of the trials were for pancreatic cancer.

“If our findings are correct and translate in humans, then we should be able to see a positive response in pancreatic cancer patients whose tumors are addicted to mutant KRAS,” Dr Sebti said.

As well as pancreatic cancer, the study authors believe these findings may also have clinical implications for colorectal and non-small cell lung cancer patients with prevalent KRAS mutations.

Source: Virginia Commonwealth University

Journal information: Kazi, A., et al. (2021) Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-20-4781.

Categories : GeneticsTags :

Researchers Uncover a Mechanism that Regulates Hair Regeneration

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Photo by engin akyurt on Unsplash

Chinese researchers have discovered a new regulatory mechanism for the regeneration capacity of skin hair, with important clues for developing treatments for hair loss. Hair loss or alopecia is an extremely common condition, yet there is still no effective therapy for it.

In the skin, activation of hair follicle stem cells (HFSCs) and progenitors by growth factor stimulation is the basis for hair follicle and hair regeneration. Hair regeneration defects can often attribute to blunted responses of HFs to growth stimuli, but it is how the sensitivity of HFSCs or progenitors to growth stimuli is determined is still unclear. Figuring out the answer to this question will provide important clues for the treatment of hair-related diseases such as alopecia.

To this end, Prof Zhang Liang’s group from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences, and collaborators uncovered the role of the micro RNA miR-24 and its mechanism in limiting the regenerative ability of hair follicle (HF) progenitors, opening up new therapeutic avenue for hair loss treatment. microRNAs regulate key steps of cell differentiation and development through suppressing gene expression in a sequence-specific manner.

The researchers discovered that that the resting-to-activation transition of HF is associated with significant down-regulation of miR-24 in HF progenitors prior to their activation.

By experimenting with mouse models, they found that miR-24 limits the sensitivity of HF progenitors to growth stimuli. miR-24 over-expression in the skin epithelium significantly delayed HF progenitor activation and hair cycle progression, while its conditional ablation significantly accelerated the hair cycle and increased the HFs’ sensitivity to growth stimuli.

Interestingly, the conditional ablation of miR-24 in skin epithelium significantly improved the effect of Minoxidil lotion on stimulating hair growths without detectable side effects, indicating that miR-24 could be a new potential target for hair regeneration therapies.

Mechanistically, the researchers discovered that Plk3 is a new miR-24 target gene that mediates the function of miR-24 to limit hair growth by regulating CCNE1, a key cell cycle regulator. They also found that miR-24 acts downstream bone morphogenetic protein (BMP), which is a known inhibitory signal for hair growth.

The study revealed that miR-24 is a key factor limiting the regenerative ability of skin HF progenitors. How adult stem cells respond appropriately to environmental stimuli is a question of fundamental importance in stem cell biology.

Source: Medical Xpress

Journal information: Fengzhen Liu et al, miR-24 controls the regenerative competence of hair follicle progenitors by targeting Plk3, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.109225

Categories : GeneticsTags :

Key Genetic Repair Protein Removes Traps

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Image source: Pixabay

Researchers have discovered that a key genetic repair protein also cleans up ‘traps’ left by another protein, its partner in genetic repair.

DNA is constantly getting damaged: the delicate strands that carry life’s genetic code take quite a beating as they jumble about in the course of their work. Errors can accumulate if left untreated, with fatal consequences — such as cancerous tumors — for the cell and the organism.

Two key proteins are involved in preventing the damage from getting out of hand: PARP — or poly ADP ribose polymerase — acts as a marker for a trouble spot, allowing XRCC1 — or X-ray repair cross-complementing protein 1 — to locate the damage and start repairs.

The repair functions of these two proteins have been known for some time. The importance of this has been recognised with the 2015 Nobel prizes for chemistry, as this knowledge allowed the development of anti-cancer drugs, known as PARP inhibitors, that disrupt the growth of certain kinds of tumours.

Although these key proteins had been identified, their precise roles were not well understood. It took a team of scientists at Tokyo Metropolitan University, the University of Sussex, and Kyoto University to revealed how exactly XRCC1 accomplishes its work — and it was a surprising discovery.

“PARP turns out to be something of a villain,” explained Kouji Hirota at Tokyo Metropolitan. “The spots it marks become ‘PARP traps’, which left un-repaired lead to disfunction and cell death.”

It seems that XRCC1 doesn’t just simply repair DNA, it goes about disarming PARP traps. The scientists compared cells without the XRCC1 gene to those without PARP as well as to still others which lacked both proteins. The team found that without XRCC1 on patrol, PARP traps accumulate like landmines.

“PARP exerts toxic effects in the cell and XRCC1 suppresses this toxicity,” Hirota elaborated.

The team aims to further explore these processes, with the goal of aiding development of future cancer treatments.

KyotoU’s Shunichi Takeda said: “These results indicate that XRCC1 is a critical factor in the resolution of PARP traps and may be a determinant of the therapeutic effect of PARP inhibitors used in the treatment of hereditary breast and ovarian cancer syndromes.”

Source: Kyoto University

Journal reference: Demin, A. A., et al. (2021) XRCC1 prevents toxic PARP1 trapping during DNA base excision repair. Molecular Cell. doi.org/10.1016/j.molcel.2021.05.009.

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Gene Drive to Control Mosquito-borne Disease a Step Closer

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Image source: Ekamalev at Unsplash

Scientists have developed a set of tools that will help create a gene drive to control mosquito-borne diseases such as the West Nile virus, which has received less attention than controlling mosquitoes that transmit malaria.

Since the advent of CRISPR genetic editing revolution, scientists have been working to use the technology to develop gene drives that target pathogen-spreading mosquitoes such as Anopheles and Aedes species, which spread malaria, dengue and other life-threatening diseases.

Much less genetic engineering work has focused on Culex genus mosquitoes, which spread devastating afflictions stemming from West Nile virus, as well as other viruses such as the Japanese encephalitis virus (JEV). Culex mosquitoes are a significant health risk in Africa and Asia, where they transmit the worm causing filariasis, a disease that can lead to a chronic debilitating condition known as elephantiasis.

University of California San Diego scientists have now developed a number of genetic editing tools that will help create a gene drive designed to stop Culex mosquitoes from spreading disease. Gene drives are designed to spread modified genes, in this case those that disable the ability to transmit pathogens, throughout the targeted wild population. The new study is published in the journal Nature Communications,

The researchers developed a Cas9/guide-RNA expression ‘toolkit’ designed for Culex mosquitoes. Since so little genetic engineering work has been done on Culex mosquitoes, the researchers were required to develop their toolkit from scratch, starting with a careful examination of the Culex genome.

“My coauthors and I believe that our work will be impactful for scientists working on the biology of the Culex disease vector since new genetic tools are deeply needed in this field,” said Gantz, an assistant research scientist in the Division of Biological Sciences at UC San Diego. “We also believe the scientific community beyond the gene drive field will welcome these findings since they could be of broad interest.”

The researchers also demonstrated the applicability of their tools in other insects.

“These modified gRNAs can increase gene drive performance in the fruit fly and could potentially offer better alternatives for future gene drive and gene-editing products in other species,” said Gantz.

Gantz and his colleagues have now tested their new tools to ensure proper genetic expression of the CRISPR components and are now on the verge of applying them to a gene drive in Culex mosquitoes. This could be used to stop pathogen transmission by Culex mosquitoes, or alternatively employed to suppress the mosquito population to prevent biting.

Source: University of California San Diego