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Study furthers radically new view of gene control

Study furthers radically new view of gene control

In recent years, MIT scientists have developed a new model for how key genes are controlled that suggests the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates. These droplets occur only at certain sites on the genome, helping to determine which genes are expressed in different types of cells.

In a new study that supports that model, researchers at MIT and the Whitehead Institute for Biomedical Research have discovered physical interactions between proteins and with DNA that help explain why these droplets, which stimulate the transcription of nearby genes, tend to cluster along specific stretches of DNA known as super-enhancers. These enhancer regions do not encode proteins but instead, regulate other genes.

“This study provides a fundamentally important new approach to deciphering how the ‘dark matter’ in our genome functions in gene control,” says Richard Young, an MIT professor of biology and member of the Whitehead Institute.

Young is one of the senior authors of the paper, along with Phillip Sharp, an MIT Institute Professor and member of MIT’s Koch Institute for Integrative Cancer Research; and Arup K. Chakraborty, the Robert T. Haslam Professor in Chemical Engineering, a professor of physics and chemistry, and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MGH, MIT, and Harvard.

Graduate student Krishna Shrinivas and postdoc Benjamin Sabari are the lead authors of the paper, which appears in Molecular Cell on Aug. 8.

“A biochemical factory”

Every cell in an organism has an identical genome, but cells such as neurons or heart cells express different subsets of those genes, allowing them to carry out their specialized functions. Previous research has shown that many of these genes are located near super enhancers, which bind to proteins called transcription factors that stimulate the copying of nearby genes into RNA.

About three years ago, Sharp, Young, and Chakraborty joined forces to try to model the interactions that occur at enhancers. In a 2017 Cell paper, based on computational studies, they hypothesized that in these regions, transcription factors form droplets called phase-separated condensates. Similar to droplets of oil suspended in salad dressing, these condensates are collections of molecules that form distinct cellular compartments but have no membrane separating them from the rest of the cell.

In a 2018 Science paper, the researchers showed that these dynamic droplets do form at super enhancer locations. Made of clusters of transcription factors and other molecules, these droplets attract enzymes such as RNA polymerases that are needed to copy DNA into messenger RNA, keeping gene transcription active at specific sites.

“We had demonstrated that the transcription machinery forms liquid-like droplets at certain regulatory regions on our genome, however we didn’t fully understand how or why these dewdrops of biological molecules only seemed to condense around specific points on our genome,” Shrinivas says.

As one possible explanation for that site specificity, the research team hypothesized that weak interactions between intrinsically disordered regions of transcription factors and other transcriptional molecules, along with specific interactions between transcription factors and particular DNA elements, might determine whether a condensate forms at a particular stretch of DNA. Biologists have traditionally focused on “lock-and-key” style interactions between rigidly structured protein segments to explain most cellular processes, but more recent evidence suggests that weak interactions between floppy protein regions also play an important role in cell activities.

In this study, computational modeling and experimentation revealed that the cumulative force of these weak interactions conspire together with transcription factor-DNA interactions to determine whether a condensate of transcription factors will form at a particular site on the genome. Different cell types produce different transcription factors, which bind to different enhancers. When many transcription factors cluster around the same enhancers, weak interactions between the proteins are more likely to occur. Once a critical threshold concentration is reached, condensates form.

“Creating these local high concentrations within the crowded environment of the cell enables the right material to be in the right place at the right time to carry out the multiple steps required to activate a gene,” Sabari says. “Our current study begins to tease apart how certain regions of the genome are capable of pulling off this trick.”

These droplets form on a timescale of seconds to minutes, and they blink in and out of existence depending on a cell’s needs.

“It’s an on-demand biochemical factory that cells can form and dissolve, as and when they need it,” Chakraborty says. “When certain signals happen at the right locus on a gene, the condensates form, which concentrates all of the transcription molecules. Transcription happens, and when the cells are done with that task, they get rid of them.”

A new view

Weak cooperative interactions between proteins may also play an important role in evolution, the researchers proposed in a 2018 Proceedings of the National Academy of Sciences paper. The sequences of intrinsically disordered regions of transcription factors need to change only a little to evolve new types of specific functionality. In contrast, evolving new specific functions via “lock-and-key” interactions requires much more significant changes.

“If you think about how biological systems have evolved, they have been able to respond to different conditions without creating new genes. We don’t have any more genes that a fruit fly, yet we’re much more complex in many of our functions,” Sharp says. “The incremental expanding and contracting of these intrinsically disordered domains could explain a large part of how that evolution happens.”

Similar condensates appear to play a variety of other roles in biological systems, offering a new way to look at how the interior of a cell is organized. Instead of floating through the cytoplasm and randomly bumping into other molecules, proteins involved in processes such as relaying molecular signals may transiently form droplets that help them interact with the right partners.

“This is a very exciting turn in the field of cell biology,” Sharp says. “It is a whole new way of looking at biological systems that is richer and more meaningful.”

Some of the MIT researchers, led by Young, have helped form a company called Dewpoint Therapeutics to develop potential treatments for a wide variety of diseases by exploiting cellular condensates. There is emerging evidence that cancer cells use condensates to control sets of genes that promote cancer, and condensates have also been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease.

Materials provided by Massachusetts Institute of Technology

Genomic data show how fish fare in evolutionary rapids

Genomic data show how fish fare in evolutionary rapids

Over recent decades, many commercially harvested fish have grown slower and matured earlier, which can translate into lower yields and a reduced resilience to overexploitation.

Scientists have long suspected that rapid evolutionary change in fish is caused by intense harvest pressure. Now, for the first time, scientists have unraveled genomic changes that prompt fisheries-induced evolution – changes that previously had been invisible to researchers, according to a study published in Science, Aug. 2.

“Most people think of evolution as a very slow process that unfolds over millennial time scales, but evolution can, in fact, happen very quickly,” said lead author Nina Overgaard Therkildsen, Cornell assistant professor of conservation genomics in the Department of Natural Resources.

In heavily exploited fish stocks, fishing almost always targets the largest individuals. “Slower-growing fish will be smaller and escape the nets better, thereby having a higher chance of passing their genes on to the next generations. This way, fishing can cause rapid evolutionary change in growth rates and other traits,” said Therkildsen. “We see many indications of this effect in wild fish stocks, but no one has known what the underlying genetic changes were.”

Therkildsen and her colleagues took advantage of an influential experiment published back in 2002. Six populations of Atlantic silversides, a fish that grows no bigger than 6 inches in length, had been subjected to intense harvesting in the lab. In two populations, the largest individuals were removed; in another two populations, the smallest individuals were removed; and in the final two populations, the fishing was random with respect to size.

After only four generations, these different harvest regimes had led to evolution of an almost two-fold difference in adult size between the groups. Therkildsen and her team sequenced the full genome of almost 900 of these fish to examine the DNA-level changes responsible for these striking shifts.

The team identified hundreds of different genes across the genome that changed consistently between populations selected for fast and slow growth. They also observed large linked-blocks of genes that changed in concert, dramatically shifting the frequencies of hundreds of genes all at the same time.

Surprisingly, however, these large shifts only happened in some of the populations, according to the new paper. This means that there were multiple genomic solutions for the fish in this experiment to get either larger or smaller.

“Some of these changes are easier to reverse than others, so to predict the impacts of fisheries-induced evolution, it is not enough to track growth rates alone, we need to monitor changes at the genomic level” said Therkildsen.

When the experiment was originally conducted nearly two decades ago by co-authors David Conover, professor of biology at the University of Oregon, and Stephan Munch of the National Marine Fisheries Service, the tools to study the genomic basis of the rapid fisheries-induced evolution they observed were not available. Fortunately, Conover and Munch had the foresight to store the samples in a freezer, making it possible to now return – armed with modern DNA sequencing tools – and reveal the underlying genomic shifts.

Research like this can assess human impacts, and improve humanity’s understanding of “the speed, consequences and reversibility of complex adaptations as we continue to sculpt the evolutionary trajectories of the species around us,” Therkildsen said.

The good news for the Atlantic silversides is that the fisheries selection was able to tap into the large reservoir of genetic variation that exists across the natural range of this species from Florida into Canada, said Therkildsen: “That genetic bank fueled rapid adaptation in the face of strong fishing pressure. Similar responses may occur in response to climate-induced shifts in other species with large genetic variability.”

In addition to Conover and Munch, contributors to “Contrasting Genomic Shifts Underlie Parallel Phenotypic Evolution in Response to Fishing” included former Cornell postdoctoral researcher Aryn P. Wilder, now a researcher at San Diego Zoo Institute for Conservation Research; Hannes Baumann, University of Connecticut; and Stephen R. Palumbi, Stanford University. This work was funded by the National Science Foundation.

Materials provided by the Cornell University

carolina dog

Researchers find out the genetic influence behind dog ownership

A team of researchers of Swedish and British scientists conducted a study on heritability of owning a dog with the help of 35,035 twin pairs from the Swedish Twin Registry. This recent study says that the adaptability of the type of dogs depends heavily on the owner’s genes. Dogs were the first animals whom humans made their pet. The relationships of dogs with humans have been intact from the past 15,000 years. The researchers compared the genes with that of twins to that of the dog owners and the result was published for the first time in the Scientific Reports journal.

The main motive of this project was to see if the dog ownership had more impact of heredity or not. The results were surprising and the scientists noticed that the genes of a person had a greater impact on whether they owned a dog. This is the main reason why dogs and humans have shared a good relationship for so many years. Though pets are common in the households and dogs are more common but the impact in the owner’s health and life due to their presence is unknown or known very little.

Tove Fall, the lead author of this study and a Professor in Molecular Epidemiology at  Uppsala University said that some of the people take very good care of their pets than many other people. Carri Westgarth, a lecturer in the field of human-animal interaction at the University of Liverpool and the co-author of the study added that this study is important as it can explain the supposed health benefits of owning a dog.

The study of twins is a well-known method for dissecting the influences of environment and genes on biology and behaviour. It is said that identical twins share an entire genome whereas non-identical twins on average share only half of the genetic variation and comparisons of the within-pair concordance of dog ownership within groups will reveal whether genetics play a role in owning a dog or not.

The scientists found the concordance rates of dog owners to be much larger in identical twins than that of the nonidentical ones and genes does play in the choice whether to own a dog or not. Which genes play an important role is not yet known and it is said that decades of archaeological research has helped in constructing a better relationship with the dogs.

The next step for the scientists is to find out the exact genetic variant responsible for an individual’s choices. This is a huge step in understanding the long history of the domestication of dog and the genetic reasons behind it.

Insulitis Autoimmune Diseases

For the first time, scientists discover the genetic variants behind lupus

A group of scientists from the Australian National University (ANU) have found that for the first time that very rare mutation of the gene is responsible for lupus. This is being considered as a groundbreaking discovery and it will change the understanding of the disease. It will also bring a change in the diagnosis and treatment of the disease which will be saving many lives. The study was published in the Nature journal.

Lupus falls in the category of the autoimmune diseases and currently, it has no cure. It mainly targets the tissues in the human body which are healthy thereby causing pain and inflammation. It can affect several parts of the body such as the heart, lungs and kidneys.

The actual cause of the disease is not properly understood by the doctors. Till now it has been known that it occurs due to a mix of the genetics and the surrounding conditions.  This understanding is now changed, thanks to a genetic breakthrough by researchers Dr. Simon Jiang, Dr. Vicki Athanasopoulos, and Professor Carola Vinuesa. It has been diagnosed mostly in women and in the age range of 15-45.

Doctor Simon Jiang, who is one of the leaders of the study is a researcher at the Centre for Personalised Immunology at Australian National University. He has been involved in the research for six years to find out the hidden genetic signals in the DNA which causes the disease. He said that they have been successful in showing for the first time how the rare variants of the gene which are present in less than one percent of the entire human population cause lupus.

He remarked that till now these rare gene variants were not considered significant in the autoimmune conditions of the human being. However, it is because of these variants that the immune system cannot function properly.

When the immune system of the body fails, it cannot distinguish between the useful microbes and bacteria, virus leading to lupus. This creates great potential for effective treatment. Dr Jiang has already started the necessary therapies in his patients which are only targeted towards the rare gene variants instead of the ones which are not specific and bring about lots of side effects in the human body.

These rare gene variants are not just responsible for lupus but they also cause other autoimmune diseases such as type 1 diabetes. This will also help in finding the severity of the disease. This disease is very difficult to diagnose properly since there are a lot of similar symptoms but they are actually not lupus.

It is also a personal achievement for Dr Jiang since he has seen many patients suffering from autoimmune diseases die due to unavailability of proper treatment.

boy treated with gene therapy

Scientists cure “bubble boy” disease with help of an improved gene therapy

Researchers declared that ten newborn children with a rare genetic disorder, the “bubble boy disease” were cured with the help of gene therapy.

With the help of this treatment, the babies have been cured of the disorder without any side effects or post-treatment complications. Scientists carrying out research hoped for this result for decades but had always received setbacks until now.

In 2003, researchers tried to use gene therapy for treating Severe Combined Immunodeficiency Disease, but they stopped midway as it was detected that the therapy gave them cancer. The present treatment does not come with any such dangerous side effects and scientists hope that it can be used for other rare diseases too such as sickle cell disease.

Children born with SCID did not have a properly working immune system and without receiving any treatment they did not even make it past their first birthday. Even simple illnesses such as common cold were fatal for these children. These children were kept in very protected environments and it gave rise to the name “bubble boy“. However, a boost in the mortality rate has been observed recently owing to the advanced detection tests and treatments such as bone marrow transplants. Unfortunately, even these treatments have complications and they make the patients dependent on regular dosages of immunoglobulin.

The latest gene therapy has been developed by St. Jude Children’s Research Hospital and UCSF Benioff Children’s Hospital based in San Francisco. The therapy rectifies the genetic defects which are there in the DNA of the babies just after they are born, which helps the body to develop the parts of the immune system that are missing.

After the extraction of blood stem cells from the bone marrow of the infants, researchers used a virus as a means of transport to send the corrected version of the defective gene to the stem cells of the patients. The rectified cells were reinfused into the body of the patients where the proliferation of the cells took place to grow healthy immune cells.

Scientists took special care in not enabling the genes which cause cancer, so they added “insulators” with the virus such that surrounding genes would not get affected when the virus is inserted into DNA. Apart from this, the patients were also given chemotherapy to a small extent for clearing the existing cells from the bone marrow so that proliferation of the corrected cells can occur in a better way.

It was an emotional day for the announcement at the St. Jude Children’s Research Hospital, as the team leader Brian Sorrentino had spent his last days fighting against his cancer to finish the work on the treatment.

Cancer cells death

Researchers find mini organs inside cancer cells resisting treatment

All over the world, scientists are constantly trying to develop more effective ways to fight cancer. But as the search for a fast and painless cure continues, new diseases and their problems come up. Scientists have identified that some of the cancer cells have been developing their own set of mini stomach, small intestine and duodenum. This is an indication of the plasticity of the cells which leads to the possibility of tumors being resistant to the drugs used to treat them. The study has been published in the Developmental Cell journal.

Purushothama Rao Tata, principal author of the study and an assistant professor at the Duke University School of Medicine commented on the nature of the cancer cells. He said that the cancer cells will be doing whatever needed for their survival. Some of the infected lung cells on being treated with chemotherapy stop some of the important cell regulators and take up the characteristics of the other cells so as to develop resistance.

Professor Tata’s team focused on the study of lung cells which are infected with cancer. Researchers used the information from the Cancer Genome Atlas Research Network and found out that a very large number of the non-small tumors of cell lung cancer do not possess the gene which indicates lung lineage named as NKX2-1. But the cells did show many of the genes which are present in the esophagus and gastrointestinal organs. As NKX2-1 was absent, it allowed the cancer cells to take on the characteristics which are associated with the other cells. Even though they were present in the lungs, the cells produced digestive enzymes.

The gene NKX2-1 is like a master control which actually guides the gene network and sets up a course for the network of lung cells. For their own development and growth, they use the genes from the same set of parent cells which are present in the stomach. Hence as the master control was absent, scientists wondered if they could make the cells form tumors by doing some manipulation. So they did tweak the cells genetically, where besides knocking down NKX2-1, they also activated the oncogenes, SOX2, KRAS.

The research work found out that the mice which had mutations of SOX2 superimposed on them developed the kind of tumors which actually resembled those of the foregut. On the other hand, those with KRAS mutations developed tumors which resembled those of the mid and hindgut.

The research work shows that cancer cells can shift the order so as to develop resistance towards the treatment but the mechanism by which it occurred was not known. More studies are to be conducted which cement these findings and develop a treatment to combat it.

Mark and Scott Kelly at the Johnson Space Center

NASA’s Twin Study reports changes in human body during spaceflight

Spending a year on the space station has a great impact on the human body but the normal body functions get restored after returning to Earth. Human beings were not evolved to be able to float in microgravity or to survive under the influence of radiation levels in space.

NASA astronaut, Scott Kelly spent almost an year on International Space Station in a mission launched in 2015. His body was subjected to incredible stress, accumulation of fluids in upper body and head led to the swelling of these parts, his genes were activated in unusual ways and his immune system went to overdrive compared to his identical twin brother, Mark Kelly. Both the brothers have been in space, but Mark remained on Earth during Scott’s mission. As time passed, Scott experienced reduced body mass, genome instability, major swelling in his blood vessels, shifts in metabolism and changes in his microbiome and also a increase in the length of telomeres.

A group of ten teams were working on NASA‘s Twin Study which included 84 researchers from 12 universities. They followed the brother duo, during and after the flight got over and tracked the change in the bodies of the brothers over the entire course of the study. Though the scope of the research was limited, this data will be very valuable when scientists plan to send astronauts on long duration spaceflights.

Because of the small sample size, there was no interest in the Twins’ Study for many years after both of them got selected as astronauts in 1996. But after Scott Kelly’s record breaking stay in space station, the discussion gathered steam and a proper study was undertaken whose full report will be soon published. Mike Snyder, the head of genetics at Stanford University and a co-author of the Twins’ Study said that this will be the first in-depth study of the people in space at a biochemical level.

A lot of interesting changes have been noticed in the twins’ genes. There are no changes in the DNA, but there have been changes in the genes which are activated to synthesize proteins. Researchers did not compare the genes of the brothers directly but rather compared the changes in the genes’ expression. As soon as Scott went into space, there was a huge shift in the over 1000 genes which change dynamically. This shows the response of the body to a completely different environment.

The most curious finding was that of the lengthening of telomeres. Telomeres are the chromosome ends which shorten as we get older. Although the telomeres returned to the same average length on his return to Earth.

The integrated report from the Twins Study researchers was released in the Science journal.

3d depiction of dna string

Studies find that poverty not only affects health but it also alters genes

In our human history, we all know very well about the circumstances of rags to riches story. There are lots of causes behind being rich as well as living in poverty. It affects not only our health but also our internal expressions as per our financial conditions. As per a recent research on poverty, the effect comes to our DNA that nearly ten percent of our genome can be affected due to poverty.

Some researchers from US and Canada have arrived at this remarkable statistic by conducting a genome-wide analysis on just under 500 participants in the Philippine-based Cebu Longitudinal Health and Nutrition Survey.

A new study challenges the current understanding of genes as immutable features of biology which are fixed at conception. Past research works have shown that social-economic status is an important determinant of human health and disease.

In other words, poverty can affect up to 10 percent of the genes in the genome. As per the latest research and study about poverty we can guess about our internal inadequacy in our inside body that results in the recession in our cells and tissues which are responsible for our diseases and overall health.

Researchers have found as evidence that poverty can become embedded across wide swaths of the genome. Lower socioeconomic status has been associated with DNA methylene levels which is a key mark that has the potential to shape gene expression at more than 2500 sites, across more than 1500 genes.

The evidence concludes that poverty is also one of the main causes of our diseases that can’t be stopped very soon and easily. It makes us crippled slowly-slowly and finally diminishes.

Families who reside in a properly built home are less likely to fall prey to such diseases and are better equipped to recover from any illnesses. Mental health of individuals and family as a whole improves greatly when concerns related to physical health are not there.