A team led by researchers at Baylor College of Medicine has discovered a mechanism by which transcription factor KLF4 can help to organize chromatin, thus influencing gene expression.
The study, published in the journal Nature Communications, reveals that the binding of KLF4 can cause DNA to condense into a separate liquid phase in a process called biomolecular condensation, which recruits other factors that influence gene expression.
“Cells regulate the expression of their genes with proteins called transcription factors,” said co-corresponding author Dr. Josephine C. Ferreon, assistant professor of pharmacology and chemical biology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “In the current study, we focused on master transcription factor KLF4, which is known to selectively mediate gene expression and reprogramming that determines cell fate.”
A cell’s genetic information is packed in chromatin, a complex, compact, dense structure made of DNA and proteins. Expressing a particular gene requires that the gene expression molecular machinery has access to that stretch of DNA. Transcription factors such as KLF4 are involved in reorganizing the chromatin to provide access and facilitate gene transcription, but it is not clear how this is accomplished.
By conducting experiments with cells grown in the lab, the researchers discovered that KLF4 forms droplets in the cell nucleus that recruit other transcription factors.
“Imagine mixing oil and water, how they form separate layers, or two liquid phases,” Ferreon said. “When KLF4 interacts with specific chromatin regions, it forms a condensate — a separate liquid phase — that preferentially recruits other molecules that help open the chromatin and mediate gene transcription.”
Other transcription factors participate in biomolecular condensation through unstructured protein regions, but the researchers showed that KLF4 droplets form in cells even if its unstructured regions are not present. Instead, KLF4 droplet formation depends on regions called zinc fingers, which are known to bind DNA. Single molecule fluorescence experiments show that the three KLF4 zinc fingers, which usually bind in a row to one DNA, can ‘bridge’ between two DNA molecules.
“This type of biomolecular condensation involving zinc fingers and DNA has not been seen before,” Ferreon said.
“Formation of this biomolecular condensate is strongly enhanced by a DNA modification called CpG methylation, a change that influences gene expression,” said co-corresponding author Dr. Kevin MacKenzie, associate professor of pathology and immunology and of pharmacology and chemical biology at Baylor. “Our results suggest that the local sequence of DNA and its CpG methylation state enable KLF4 to drive DNA into a separate phase, which helps to organize chromatin in three dimensions.”
“Hundreds of human transcription factors contain tandem zinc fingers like those in KLF4, so this class of rapidly evolving proteins may be implicated in chromatin organization through similar ‘bridging’ interactions,” said MacKenzie.
Other contributors to this work include Rajesh Sharma, Kyoung-Jae Choi, My Diem Quan, Sonum Sharma, Hyekyung Park, Anel LaGrone, Jean J. Kim, Allan Chris M. Ferreon and Choel Kim, all in Baylor College of Medicine, and Banumathi Sankaran in Lawrence Berkeley National Laboratory, California.
This work was supported by NIH grants R01 GM122763, R21 NS107792, R01 NS105874, R21 NS109678, R01 DK121970 and R61 HD099995. Additional support was provided by a Core Facility Support Award from the Cancer Prevention and Research Institute of Texas (grant RP160805).
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Materials provided by Baylor College of Medicine. Original written by Kaylee Dusang. Note: Content may be edited for style and length.

A technology developed at Vanderbilt University Medical Center has led to the discovery of an “ultra-potent” monoclonal antibody against multiple variants of SARS-CoV-2, the virus responsible for COVID-19, including the delta variant.
The antibody has rare characteristics that make it a valuable addition to the limited set of broadly reactive antibody therapeutic candidates, researchers reported in the journal Cell Reports.
The technology, called LIBRA-seq, has helped speed up the discovery of antibodies that can neutralize SARS-CoV-2. It also enables researchers to screen antibodies against other viruses that have not yet caused human disease but which have a high potential of doing so.
“This is one way to proactively build a repertoire of potential therapeutics” against future outbreaks, said Ivelin Georgiev, PhD, director of the Vanderbilt Program in Computational Microbiology and Immunology and associate director of the Vanderbilt Institute for Infection, Immunology and Inflammation.
“The pathogens keep evolving, and we’re basically playing catch-up,” said Georgiev, associate professor of Pathology, Microbiology & Immunology and Computer Science, and a member of the Vanderbilt Vaccine Center.
A more proactive approach that anticipates future outbreaks before they occur is needed to prevent a repeat of COVID-19, “or something worse happening in the future,” he said.

Having good room ventilation to dilute and disperse indoor air pollutants has long been recognized, and with the COVID-19 pandemic its importance has become all the more heightened. But new experiments by indoor air researchers at Lawrence Berkeley National Laboratory (Berkeley Lab) show that certain circumstances will result in poor mixing of room air, meaning airborne contaminants may not be effectively dispersed and removed by building level ventilation.
Using CO2 as a tracer to track small respiratory aerosols that travel with air currents in a room, the Berkeley Lab team found that when overhead vents (or diffusers) are supplying heated air, it created thermally stratified conditions that block the flow of clean air down to the “breathing zone” in the middle height of the room. As a result, even when people are sitting more than 6 feet from each other, some occupants may be exposed to respiratory aerosols from others at a rate 5 to 6 times higher than if the same room were well mixed. Their study, “Measured influence of overhead HVAC on exposure to airborne contaminants from simulated speaking in a meeting and a classroom,” was published recently in the journal Indoor Air.
“When everything’s well mixed, everybody’s exposed to the same conditions,” said Berkeley Lab indoor air researcher Woody Delp. “When it’s not well mixed, you can have, from a COVID perspective, potential hot spots. So, if there’s one infected individual in the room, instead of having their expelled breath fully dispersed and then then properly diluted and removed by the HVAC system, another person sitting next to them or even across the room could get a high concentration of that infected person’s emitted viral aerosol.”
Delp notes that this situation would occur only in the case of heated air being supplied from the overhead diffusers. When cold or neutral air is being supplied, the researchers did not see the thermal stratification occur; instead, the room was found to be well mixed in those circumstances.
While the basic risk from overhead heating has been known for years, it had not previously been quantified under controlled but realistic conditions of a meeting or classroom. The results are important for understanding how large the risk can be when occupants are intentionally spaced for safety. “Ventilation is essential to maintaining good air quality,” said Brett Singer, the lead author of the study and head of Berkeley Lab’s Indoor Environment Group. “But if you’re heating overhead without intentionally mixing the air in the room, you will not get the full benefit of ventilation.”
Fortunately, there is a simple solution, the study found: using portable air cleaners that pull air in from below and push it out through the top. “They take care of the mixing and then they also filter the air, so they have a double benefit,” Singer said.

It’s basic exercise knowledge that to gain muscles, you strength train, and to lose fat, you do cardio — right?
Not necessarily, a new UNSW study published this week in Sports Medicine suggests.
In fact, the study — a systematic review and meta-analysis that reviewed and analysed existing evidence — shows we can lose around 1.4 per cent of our entire body fat through strength training alone, which is similar to how much we might lose through cardio or aerobics.
“A lot of people think that if you want to lose weight, you need to go out and run,” says senior author of the study Dr Mandy Hagstrom, exercise physiologist and senior lecturer at UNSW Medicine & Health.
“But our findings show that even when strength training is done on its own, it still causes a favourable loss of body fat without having to consciously diet or go running.”
Up until now, the link between strength training and fat loss has been unclear. Studies have investigated this link in the past, but their sample sizes tend to be small — a side effect of not many people wanting to volunteer to exercise for months on end. Smaller sample sizes can make it difficult to find statistically significant results, especially as many bodies can respond differently to exercise programs.

Genetic causes of traits and diseases are being intensively researched today. And more than 250,000 such connections are now known. In many of these cases, however, it is unclear how the genetic variant found affects the corresponding trait. One possible explanation is that the genetic variant affects gene expression, that is, how the gene is read, and thus alters trait expression.
The international eQTLGen Consortium has therefore conducted large-scale research on how genetic variants influence the expression of genes in the blood. A major finding of the study was that genetic regulations were found in close proximity to the gene in 88 per cent of all the genes analysed. These are called cis effects. It was also shown that 37 per cent of the trait-related genetic variants studied were regulated by distant genes, a phenomenon called trans effects.
Mechanisms identified that determine the first occurrence of menstruation
The many cis and trans effects on gene expression found offer numerous new ways to explain molecular relationships for a wide range of traits and diseases. For example, researchers identified trans mechanisms caused by the gene ZNF131 that determine the first occurrence of menstruation. In some cases, these mechanisms have already been confirmed in the laboratory. Another such example is new mechanistic insight into how the FADS1 and FADS2 genes influence fatty acid metabolism.
“The results significantly expand our knowledge of how gene expression in the blood is regulated and go far beyond the information in databases currently available such as GTEx, the world’s largest database to date,” said Professor Markus Scholz. “We expect this to provide us a better understanding of genetic associations. Although not typical for the sciences, other study groups were already using the data from our study to interpret the genetic associations they found before it was even published,” said the Leipzig bioinformatics researcher.
Data from 7524 subjects and patients at Leipzig University’s Faculty of Medicine
The Consortium, established in 2014, included 37 studies with a total number of 31,684 subjects and patients. Leipzig University’s Faculty of Medicine contributed significantly to the overall numbers as the data analysed from its three cohorts (Sorben, LIFE Adult and LIFE Heart) came from 7524 individuals. 
The Consortium was established by researchers from the Institute of Medical Informatics, Statistics and Epidemiology (IMISE) and led by a team from the University of Groningen. The researchers also developed a comprehensive analysis plan together. “The analyses are very complex because, for one thing, several billion tests are performed and the control of the error rate has to be tailored to the type of correlations being studied,” said Dr Holger Kirsten, a researcher at IMISE.
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Whenever organic matter is burned, such as in a wildfire, a power plant, a car’s exhaust, or in daily cooking, the combustion releases polycyclic aromatic hydrocarbons (PAHs) — a class of pollutants that is known to cause lung cancer.
There are more than 100 known types of PAH compounds emitted daily into the atmosphere. Regulators, however, have historically relied on measurements of a single compound, benzo(a)pyrene, to gauge a community’s risk of developing cancer from PAH exposure. Now MIT scientists have found that benzo(a)pyrene may be a poor indicator of this type of cancer risk.
In a modeling study appearing today in the journal GeoHealth, the team reports that benzo(a)pyrene plays a small part — about 11 percent — in the global risk of developing PAH-associated cancer. Instead, 89 percent of that cancer risk comes from other PAH compounds, many of which are not directly regulated.
Interestingly, about 17 percent of PAH-associated cancer risk comes from “degradation products” — chemicals that are formed when emitted PAHs react in the atmosphere. Many of these degradation products can in fact be more toxic than the emitted PAH from which they formed.
The team hopes the results will encourage scientists and regulators to look beyond benzo(a)pyrene, to consider a broader class of PAHs when assessing a community’s cancer risk.
“Most of the regulatory science and standards for PAHs are based on benzo(a)pyrene levels. But that is a big blind spot that could lead you down a very wrong path in terms of assessing whether cancer risk is improving or not, and whether it’s relatively worse in one place than another,” says study author Noelle Selin, a professor in MIT’s Institute for Data, Systems and Society, and the Department of Earth, Atmospheric and Planetary Sciences.

Researchers at Baylor College of Medicine and Texas Children’s Hospital have uncovered a potential Achilles heel of acute myeloid leukemia (AML) in children that could lead to new treatments for this devastating disease.
The team was the first to identify specific super enhancers (SE) — regions of DNA that drive the over production of certain gene products — in cells from children with AML. These SE were associated with leukemia-promoting genes and were generally distinct from the previously published SE of adult AML. One SE of specific interest was associated with the gene RARA. Sixty-four percent of the pediatric patient AML samples the researchers studied had this RARA SE.
AML cells with a RARA SE were sensitive to treatment with the drug tamibarotene in lab cultures and in animal models, prolonging survival and reducing the leukemia burden. In contrast, AML cells without RARA SE were not sensitive to tamibarotene treatment. The findings, published in Blood Advances, support the development of a clinical trial to evaluate tamibarotene in children with AML with high RARA levels.
“Our team is interested in finding new drugs that are more effective and less toxic to treat children with AML,” said corresponding author Dr. Joanna Yi, assistant professor of pediatrics-oncology at Baylor and Texas Children’s.
Dr. Yi and her team seek to identify molecular drivers of pediatric AML that are specifically expressed in leukemia cells and absent in normal cells. “This would increase the chances of developing a more effective treatment for AML that would specifically attack the leukemia cells while having no or minimal effects on normal cells in the body,” Yi explained.
“In general, pediatric cancers are genomically quiet, meaning that, typically, few mutated genes have been associated with childhood cancers. Moreover, the mutations that have been found do not seem to be susceptible to regulation by drugs,” Yi said.
As found in other conditions, malfunctioning gene regulators can alter the production of normal gene products. For instance, super enhancer gene regulators can trigger an overabundance of a certain normal protein, which may disrupt cellular functions in ways that can lead to cancer.
Yi and her colleagues were excited to find that tamibarotene slowed the proliferation, induced apoptosis or promoted cell maturation in lab cultures of patient AML cells with the RARA SE. In contrast, cells without the RARA SE were not sensitive to the drug.
In addition, tamibarotene extended survival in an animal model of AML with RARA SE and did not slow cancer growth in an animal model lacking RARA SE.
“Our findings support taking the next step toward bringing this potential new treatment to the clinic by conducting a clinical trial of tamibarotene in children with AML having high RARA levels,” Yi said.
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The Latest on Kids and Covid VaccinesApoorva MandavilliReporting on the coronavirusChildren have a much lower risk of Covid-19 than adults, even when exposed to the Delta variant. Still, a small number of infected children develop a life-threatening condition called multi-system inflammatory syndrome in children, or MIS-C. Others may have lingering symptoms for months.And unvaccinated children, even if they do not become ill themselves, can spread the virus to family members, teachers and others they interact with regularly.

SharecloseShare pageCopy linkAbout sharingimage source, Getty ImagesThe US is to donate 500 million more doses of the Pfizer vaccine to developing nations.President Joe Biden will make the pledge at a virtual Covid-19 summit on the sidelines of the UN General Assembly, US officials have said.The additional jabs will see the total US commitment on vaccine sharing exceed one billion jabs.Experts say some 11 billion doses are required to vaccinate at least 70% of the global population.The World Health Organisation has set a minimum target of 40% vaccine coverage in every country by the end of 2021.But the goal is unlikely to be met. While many high-income countries have now given at least one shot to more than half their populations, only 2% of people in low-income countries have had their first dose, according to data from the University of Oxford.Covid vaccine tracker: How’s my country doing?Could 241m vaccine doses go to waste?Global vaccine supply is still laggingAnalysis by Stephanie Hegarty, BBC population correspondentIt’s a big pledge but it’ll be met with a fair share of scepticism from countries still waiting to vaccinate even 2% of their population.The US had already pledged 580m doses but delivered only 140m of those so far.So what’s different now? Well, global production has picked up in the past few months and there are doses available.Rich countries could have 1.2bn spare doses by the end of the year, even if they run booster campaigns, according to science analytics firm Airfinity. 241m of those could go to waste if they’re not donated. But these need to be sent very soon.Covax, the WHO-backed scheme to help distribute vaccines fairly, has told the BBC that too many of the donations it’s receiving have come in small quantities, at the last minute and with little time left before they expire.That makes their job of getting them to where they are needed very hard. If Biden want to meet this ambitious goal of vaccinating the world by this time next year, that will have to change.

Eating your daily calories within a consistent window of 8-10 hours is a powerful strategy to prevent and manage chronic diseases such as diabetes and heart disease, according to a new manuscript published in the Endocrine Society’s journal, Endocrine Reviews.
Time-restricted eating is a type of intermittent fasting that limits your food intake to a certain number of hours each day. Intermittent fasting is one of the most popular diet trends, and people are using it to lose weight, improve their health and simplify their lifestyles.
“People who are trying to lose weight and live a healthier lifestyle should pay more attention to when they eat as well as what they eat. Time-restricted eating is an easy-to-follow and effective dietary strategy that requires less mental math than counting calories,” said Satchidananda Panda, Ph.D., of the Salk Institute for Biological Studies in La Jolla, Calif. “Intermittent fasting can improve sleep and a person’s quality of life as well as reduce the risk of obesity, diabetes and heart disease.”
In the manuscript, the researchers explore the science behind time-restricted eating, recent clinical studies and the scope for future research to better understand its health benefits. Recent research has revealed that genes, hormones and metabolism rise and fall at different times of the 24-hour day. Aligning our daily habit of when we eat with the body’s internal clock can optimize health and reduce the risk or disease burden of chronic conditions like diabetes, heart disease and liver disease.
“Eating at random times breaks the synchrony of our internal program and make us prone to diseases,” said Panda. “Intermittent fasting is a lifestyle that anyone can adopt. It can help eliminate health disparities and lets everyone live a healthy and fulfilling life.”
Other authors of the study include: Emily Manoogian of the Salk Institute for Biological Studies; Lisa Chow of the University of Minnesota in Minneapolis, Minn.; Pam Taub of the University of California, San Diego, in La Jolla, Calif.; and Blandine Laferrère of the Columbia University Irving Medical Center in New York, N.Y.
The study received funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging, the National Cancer Institute, the Larry l. Hillblom Foundation, the Wu Tsai Human Performance Alliance, the U.S. Department of Defense and the Federal Emergency Management Agency.
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