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Liu Y.,Center for the Physics of Living Cells | Liu Y.,University of Illinois at Urbana - Champaign | Hsin J.,Center for the Physics of Living Cells | Hsin J.,University of Illinois at Urbana - Champaign | And 4 more authors.
Biophysical Journal | Year: 2011

The molecular motor protein myosin VI moves toward the minus-end of actin filaments with a step size of 30-36 nm. Such large step size either drastically limits the degree of complex formation between dimer subunits to leave enough length for the lever arms, or requires an extension of the lever arms' crystallographically observed structure. Recent experimental work proposed that myosin VI dimerization triggers the unfolding of the protein's proximal tail domain which could drive the needed lever-arm extension. Here, we demonstrate through steered molecular dynamics simulation the feasibility of sufficient extension arising from turning a three-helix bundle into a long α-helix. A key role is played by the known calmodulin binding that facilitates the extension by altering the strain path in myosin VI. Sequence analysis of the proximal tail domain suggests that further calmodulin binding sites open up when the domain's three-helix bundle is unfolded and that subsequent calmodulin binding stabilizes the extended lever arms. © 2011 by the Biophysical Society.


Yoo J.,University of Illinois at Urbana - Champaign | Yoo J.,Center for the Physics of Living Cells | Aksimentiev A.,University of Illinois at Urbana - Champaign | Aksimentiev A.,Center for the Physics of Living Cells | Aksimentiev A.,Beckman Institute for Advanced Science and Technology
Journal of Physical Chemistry B | Year: 2012

The concept of "ion atmosphere" is prevalent in both theoretical and experimental studies of nucleic acid systems, yet the spatial arrangement and the composition of ions in the ion atmosphere remain elusive, in particular when several ionic species (e.g., Na+, K+, and Mg 2+) compete to neutralize the charge of a nucleic acid polyanion. Complementing the experimental study of Bai and co-workers (J. Am. Chem. Soc.2007, 129, 14981), here we characterize ion atmosphere around double-stranded DNA through all-atom molecular dynamics simulations. We demonstrate that our improved parametrization of the all-atom model can quantitatively reproduce the experimental ion-count data. Our simulations determine the size of the ion atmosphere, the concentration profiles of ionic species competing to neutralize the DNA charge, and the sites of the cations-preferential binding at the surface of double-stranded DNA. We find that the effective size of the ion atmosphere depends on both the bulk concentration and valence of ions: increasing either reduces the size of the atmosphere. Near DNA, the concentration of Mg2+ is strongly enhanced compared to monovalent cations. Within the DNA grooves, the relative concentrations of cations depend on their bulk values. Nevertheless, the total charge of competing cations buried in the DNA grooves is constant and compensates for about ∼30% of the total DNA charge. © 2012 American Chemical Society.


Ha T.,Center for the Physics of Living Cells | Ha T.,University of Illinois at Urbana - Champaign | Kozlov A.G.,University of Washington | Lohman T.M.,University of Washington
Annual Review of Biophysics | Year: 2012

The advent of new technologies allowing the study of single biological molecules continues to have a major impact on studies of interacting systems as well as enzyme reactions. These approaches (fluorescence, optical, and magnetic tweezers), in combination with ensemble methods, have been particularly useful for mechanistic studies of proteinnucleic acid interactions and enzymes that function on nucleic acids. We review progress in the use of single-molecule methods to observe and perturb the activities of proteins and enzymes that function on flexible single-stranded DNA. These include single-stranded DNA binding proteins, recombinases (RecARad51), and helicasestranslocases that operate as motor proteins and play central roles in genome maintenance. We emphasize methods that have been used to detect and study the movement of these proteins (both ATP-dependent directional and random movement) along the single-stranded DNA and the mechanistic and functional information that can result from detailed analysis of such movement. © 2012 by Annual Reviews. All rights reserved.


News Article | February 15, 2017
Site: news.mit.edu

MIT chemical engineers have developed an extremely sensitive detector that can track single cells’ secretion of dopamine, a brain chemical responsible for carrying messages involved in reward-motivated behavior, learning, and memory. Using arrays of up to 20,000 tiny sensors, the researchers can monitor dopamine secretion of single neurons, allowing them to explore critical questions about dopamine dynamics. Until now, that has been very difficult to do. “Now, in real-time, and with good spatial resolution, we can see exactly where dopamine is being released,” says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering and the senior author of a paper describing the research, which appears in the Proceedings of the National Academy of Sciences the week of Feb. 6. Strano and his colleagues have already demonstrated that dopamine release occurs differently than scientists expected in a type of neural progenitor cell, helping to shed light on how dopamine may exert its effects in the brain. The paper’s lead author is Sebastian Kruss, a former MIT postdoc who is now at Göttingen University, in Germany. Other authors are Daniel Salem and Barbara Lima, both MIT graduate students; Edward Boyden, an associate professor of biological engineering and brain and cognitive sciences, as well as a member of the MIT Media Lab and the McGovern Institute for Brain Research; Lela Vukovic, an assistant professor of chemistry at the University of Texas at El Paso; and Emma Vander Ende, a graduate student at Northwestern University. Dopamine is a neurotransmitter that plays important roles in learning, memory, and feelings of reward, which reinforce positive experiences. Neurotransmitters allow neurons to relay messages to nearby neurons through connections known as synapses. However, unlike most other neurotransmitters, dopamine can exert its effects beyond the synapse: Not all dopamine released into a synapse is taken up by the target cell, allowing some of the chemical to diffuse away and affect other nearby cells. “It has a local effect, which controls the signaling through the neurons, but also it has a global effect,” Strano says. “If dopamine is in the region, it influences all the neurons nearby.” Tracking this dopamine diffusion in the brain has proven difficult. Neuroscientists have tried using electrodes that are specialized to detect dopamine, but even using the smallest electrodes available, they can place only about 20 near any given cell. “We’re at the infancy of really understanding how these packets of chemicals move and their directionality,” says Strano, who decided to take a different approach. Strano’s lab has previously developed sensors made from arrays of carbon nanotubes — hollow, nanometer-thick cylinders made of carbon, which naturally fluoresce when exposed to laser light. By wrapping these tubes in different proteins or DNA strands, scientists can customize them to bind to different types of molecules. The carbon nanotube sensors used in this study are coated with a DNA sequence that makes the sensors interact with dopamine. When dopamine binds to the carbon nanotubes, they fluoresce more brightly, allowing the researchers to see exactly where the dopamine was released. The researchers deposited more than 20,000 of these nanotubes on a glass slide, creating an array that detects any dopamine secreted by a cell placed on the slide. In the new PNAS study, the researchers used these dopamine sensors to explore a longstanding question about dopamine release in the brain: From which part of the cell is dopamine secreted? To help answer that question, the researchers placed individual neural progenitor cells known as PC-12 cells onto the sensor arrays. PC-12 cells, which develop into neuron-like cells under the right conditions, have a starfish-like shape with several protrusions that resemble axons, which form synapses with other cells. After stimulating the cells to release dopamine, the researchers found that certain dopamine sensors near the cells lit up immediately, while those farther away turned on later as the dopamine diffused away. Tracking those patterns over many seconds allowed the researchers to trace how dopamine spreads away from the cells. Strano says one might expect to see that most of the dopamine would be released from the tips of the arms extending out from the cells. However, the researchers found that in fact more dopamine came from the sides of the arms. “We have falsified the notion that dopamine should only be released at these regions that will eventually become the synapses,” Strano says. “This observation is counterintuitive, and it’s a new piece of information you can only obtain with a nanosensor array like this one.” The team also showed that most of the dopamine traveled away from the cell, through protrusions extending in opposite directions. “Even though dopamine is not necessarily being released only at the tip of these protrusions, the direction of release is associated with them,” Salem says. Other questions that could be explored using these sensors include how dopamine release is affected by the direction of input to the cell, and how the presence of nearby cells influences each cell’s dopamine release. The research was funded by the National Science Foundation, the National Institutes of Health, a University of Illinois Center for the Physics of Living Cells Postdoctoral Fellowship, the German Research Foundation, and a Liebig Fellowship.


News Article | March 2, 2017
Site: www.scientificcomputing.com

MIT chemical engineers have developed an extremely sensitive detector that can track single cells’ secretion of dopamine, a brain chemical responsible for carrying messages involved in reward-motivated behavior, learning, and memory. Using arrays of up to 20,000 tiny sensors, the researchers can monitor dopamine secretion of single neurons, allowing them to explore critical questions about dopamine dynamics. Until now, that has been very difficult to do. “Now, in real-time, and with good spatial resolution, we can see exactly where dopamine is being released,” says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering and the senior author of a paper describing the research, which appears in the Proceedings of the National Academy of Sciences the week of Feb. 6. Strano and his colleagues have already demonstrated that dopamine release occurs differently than scientists expected in a type of neural progenitor cell, helping to shed light on how dopamine may exert its effects in the brain. The paper’s lead author is Sebastian Kruss, a former MIT postdoc who is now at Göttingen University, in Germany. Other authors are Daniel Salem and Barbara Lima, both MIT graduate students; Edward Boyden, an associate professor of biological engineering and brain and cognitive sciences, as well as a member of the MIT Media Lab and the McGovern Institute for Brain Research; Lela Vukovic, an assistant professor of chemistry at the University of Texas at El Paso; and Emma Vander Ende, a graduate student at Northwestern University. Dopamine is a neurotransmitter that plays important roles in learning, memory, and feelings of reward, which reinforce positive experiences. Neurotransmitters allow neurons to relay messages to nearby neurons through connections known as synapses. However, unlike most other neurotransmitters, dopamine can exert its effects beyond the synapse: Not all dopamine released into a synapse is taken up by the target cell, allowing some of the chemical to diffuse away and affect other nearby cells. “It has a local effect, which controls the signaling through the neurons, but also it has a global effect,” Strano says. “If dopamine is in the region, it influences all the neurons nearby.” Tracking this dopamine diffusion in the brain has proven difficult. Neuroscientists have tried using electrodes that are specialized to detect dopamine, but even using the smallest electrodes available, they can place only about 20 near any given cell. “We’re at the infancy of really understanding how these packets of chemicals move and their directionality,” says Strano, who decided to take a different approach. Strano’s lab has previously developed sensors made from arrays of carbon nanotubes — hollow, nanometer-thick cylinders made of carbon, which naturally fluoresce when exposed to laser light. By wrapping these tubes in different proteins or DNA strands, scientists can customize them to bind to different types of molecules. The carbon nanotube sensors used in this study are coated with a DNA sequence that makes the sensors interact with dopamine. When dopamine binds to the carbon nanotubes, they fluoresce more brightly, allowing the researchers to see exactly where the dopamine was released. The researchers deposited more than 20,000 of these nanotubes on a glass slide, creating an array that detects any dopamine secreted by a cell placed on the slide. In the new PNAS study, the researchers used these dopamine sensors to explore a longstanding question about dopamine release in the brain: From which part of the cell is dopamine secreted? To help answer that question, the researchers placed individual neural progenitor cells known as PC-12 cells onto the sensor arrays. PC-12 cells, which develop into neuron-like cells under the right conditions, have a starfish-like shape with several protrusions that resemble axons, which form synapses with other cells. After stimulating the cells to release dopamine, the researchers found that certain dopamine sensors near the cells lit up immediately, while those farther away turned on later as the dopamine diffused away. Tracking those patterns over many seconds allowed the researchers to trace how dopamine spreads away from the cells. Strano says one might expect to see that most of the dopamine would be released from the tips of the arms extending out from the cells. However, the researchers found that in fact more dopamine came from the sides of the arms. “We have falsified the notion that dopamine should only be released at these regions that will eventually become the synapses,” Strano says. “This observation is counterintuitive, and it’s a new piece of information you can only obtain with a nanosensor array like this one.” The team also showed that most of the dopamine traveled away from the cell, through protrusions extending in opposite directions. “Even though dopamine is not necessarily being released only at the tip of these protrusions, the direction of release is associated with them,” Salem says. Other questions that could be explored using these sensors include how dopamine release is affected by the direction of input to the cell, and how the presence of nearby cells influences each cell’s dopamine release. The research was funded by the National Science Foundation, the National Institutes of Health, a University of Illinois Center for the Physics of Living Cells Postdoctoral Fellowship, the German Research Foundation, and a Liebig Fellowship.


News Article | November 14, 2016
Site: www.eurekalert.org

Nature is full of parasites--organisms that flourish and proliferate at the expense of another species. Surprisingly, these same competing roles of parasite and host can be found in the microscopic molecular world of the cell. A new study by two Illinois researchers has demonstrated that dynamic elements within the human genome interact with each other in a way that strongly resembles the patterns seen in populations of predators and prey. The findings, published in Physical Review Letters by physicists Chi Xue and Nigel Goldenfeld, (DOI: 10.1103/PhysRevLett.117.208101) are an important step toward understanding the complex ways that genomes change over the lifetime of individual organisms, and how they evolve over generations. "These are genes that are active and are doing genome editing in real time in living cells, and this is a start of trying to really understand them in much more detail than has been done before," said Goldenfeld, who leads the Biocomplexity research theme at the Carl R. Woese Institute for Universal Biology (IGB). "This is helping us understand the evolution of complexity and the evolution of genomes." The study was supported by Center for the Physics of Living Cells, a Physics Frontiers Center at Illinois supported by the National Science Foundation, and the NASA Astrobiology Institute for Universal Biology at Illinois, which Goldenfeld directs. Goldenfeld and Xue embarked on this work because of their interest in transposons, small regions of DNA that can move themselves from one part of the genome to another during the lifetime of a cell--a capability that has earned them the name "jumping genes." Collectively, various types of transposons make up almost half of the human genome. When they move around, they may create mutations in or alter the activity of a functional gene; transposons can therefore create new genetic profiles in a population for natural selection to act on, in either a positive or negative way. The Illinois researchers wanted to learn more about how evolution works on this level, the level of whole organisms, by looking at the metaphorical ecosystem of the human genome. In this view, the physical structure of the DNA that makes up the genome acts like an environment, in which two types of transposons, long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), have a competitive relationship with one another. In order to replicate, SINEs steal the molecular machinery that LINEs use to copy themselves, somewhat like a cuckoo bird tricks other birds into raising her chicks for her while abandoning their own. With help from Oleg Simakov, a researcher at the Okinawa Institute of Science and Technology, Xue and Goldenfeld focused on the biology of L1 elements and Alu elements, respectively common types of LINEs and SINEs in the human genome. The researchers adopted methods from modern statistical physics and modeled the interaction between Alu and L1 elements mathematically as a stochastic process--a process created from chance interactions. This method has been successfully applied in ecology to describe predator-prey interactions; Xue and Goldenfeld simulated the movements of transposons within the human genome with the same mathematical method. Their models included a detailed accounting for how Alu elements steal the molecular machinery L1 elements use to copy themselves. Xue and Goldenfeld's results predicted that populations of LINE and SINE elements in the genome are expected to oscillate the way those of, for example, wolves and rabbits might. "We realized that the transposons' interaction actually was pretty much like the predator-prey interaction in ecology," said Xue. "We came up with the idea, why don't we apply the same idea of predator-prey dynamics . . .we expected to see the oscillations we see in the predator-prey model. So we first did the simulation and we saw the oscillations we expected, and we got really excited." In other words, too many SINEs and the LINEs start to suffer, and soon there are not enough for all the SINEs to exploit. SINEs start to suffer, and the LINEs make a come-back. Xue and Goldenfeld's model made the surprising prediction that these oscillations occur over a timescale that is longer than the human lifespan--waves of Alu elements and L1 elements pushing and pulling at each other in slow motion across generations of the human genomes that carry them. "The most enlightening aspect of the study for me was the fact that we could really compute the timescales, and see that it is possible that we could observe these things," said Goldenfeld. "We have a prediction for what happens in single cells, and we may be able to actually do an experiment to observe these things, though the period is longer than the lifetime of a single cell." In a related study, Goldenfeld's laboratory has collaborated with the laboratory of fellow physicist and IGB Biocomplexity research theme member Thomas Kuhlman to visualize the movements of transposons within the genomes of living cells. Using this type of innovative technology, and by studying the history of molecular evolution in other species, Goldenfeld and Xue hope to test some of the predictions made by their model and continue to gain insight into the dynamic world of the genome.


News Article | November 15, 2016
Site: www.biosciencetechnology.com

Nature is full of parasites--organisms that flourish and proliferate at the expense of another species. Surprisingly, these same competing roles of parasite and host can be found in the microscopic molecular world of the cell. A new study by two Illinois researchers has demonstrated that dynamic elements within the human genome interact with each other in a way that strongly resembles the patterns seen in populations of predators and prey. The findings, published in Physical Review Letters by physicists Chi Xue and Nigel Goldenfeld, (DOI: 10.1103/PhysRevLett.117.208101) are an important step toward understanding the complex ways that genomes change over the lifetime of individual organisms, and how they evolve over generations. "These are genes that are active and are doing genome editing in real time in living cells, and this is a start of trying to really understand them in much more detail than has been done before," said Goldenfeld, who leads the Biocomplexity research theme at the Carl R. Woese Institute for Universal Biology (IGB). "This is helping us understand the evolution of complexity and the evolution of genomes." The study was supported by Center for the Physics of Living Cells, a Physics Frontiers Center at Illinois supported by the National Science Foundation, and the NASA Astrobiology Institute for Universal Biology at Illinois, which Goldenfeld directs. Goldenfeld and Xue embarked on this work because of their interest in transposons, small regions of DNA that can move themselves from one part of the genome to another during the lifetime of a cell--a capability that has earned them the name "jumping genes." Collectively, various types of transposons make up almost half of the human genome. When they move around, they may create mutations in or alter the activity of a functional gene; transposons can therefore create new genetic profiles in a population for natural selection to act on, in either a positive or negative way. The Illinois researchers wanted to learn more about how evolution works on this level, the level of whole organisms, by looking at the metaphorical ecosystem of the human genome. In this view, the physical structure of the DNA that makes up the genome acts like an environment, in which two types of transposons, long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), have a competitive relationship with one another. In order to replicate, SINEs steal the molecular machinery that LINEs use to copy themselves, somewhat like a cuckoo bird tricks other birds into raising her chicks for her while abandoning their own. With help from Oleg Simakov, a researcher at the Okinawa Institute of Science and Technology, Xue and Goldenfeld focused on the biology of L1 elements and Alu elements, respectively common types of LINEs and SINEs in the human genome. The researchers adopted methods from modern statistical physics and modeled the interaction between Alu and L1 elements mathematically as a stochastic process--a process created from chance interactions. This method has been successfully applied in ecology to describe predator-prey interactions; Xue and Goldenfeld simulated the movements of transposons within the human genome with the same mathematical method. Their models included a detailed accounting for how Alu elements steal the molecular machinery L1 elements use to copy themselves. Xue and Goldenfeld's results predicted that populations of LINE and SINE elements in the genome are expected to oscillate the way those of, for example, wolves and rabbits might. "We realized that the transposons' interaction actually was pretty much like the predator-prey interaction in ecology," said Xue. "We came up with the idea, why don't we apply the same idea of predator-prey dynamics . . .we expected to see the oscillations we see in the predator-prey model. So we first did the simulation and we saw the oscillations we expected, and we got really excited." In other words, too many SINEs and the LINEs start to suffer, and soon there are not enough for all the SINEs to exploit. SINEs start to suffer, and the LINEs make a come-back. Xue and Goldenfeld's model made the surprising prediction that these oscillations occur over a timescale that is longer than the human lifespan--waves of Alu elements and L1 elements pushing and pulling at each other in slow motion across generations of the human genomes that carry them. "The most enlightening aspect of the study for me was the fact that we could really compute the timescales, and see that it is possible that we could observe these things," said Goldenfeld. "We have a prediction for what happens in single cells, and we may be able to actually do an experiment to observe these things, though the period is longer than the lifetime of a single cell." In a related study, Goldenfeld's laboratory has collaborated with the laboratory of fellow physicist and IGB Biocomplexity research theme member Thomas Kuhlman to visualize the movements of transposons within the genomes of living cells. Using this type of innovative technology, and by studying the history of molecular evolution in other species, Goldenfeld and Xue hope to test some of the predictions made by their model and continue to gain insight into the dynamic world of the genome.


News Article | November 15, 2016
Site: www.sciencedaily.com

Nature is full of parasites -- organisms that flourish and proliferate at the expense of another species. Surprisingly, these same competing roles of parasite and host can be found in the microscopic molecular world of the cell. A new study by two Illinois researchers has demonstrated that dynamic elements within the human genome interact with each other in a way that strongly resembles the patterns seen in populations of predators and prey. The findings, published in Physical Review Letters by physicists Chi Xue and Nigel Goldenfeld, are an important step toward understanding the complex ways that genomes change over the lifetime of individual organisms, and how they evolve over generations. "These are genes that are active and are doing genome editing in real time in living cells, and this is a start of trying to really understand them in much more detail than has been done before," said Goldenfeld, who leads the Biocomplexity research theme at the Carl R. Woese Institute for Universal Biology (IGB). "This is helping us understand the evolution of complexity and the evolution of genomes." The study was supported by Center for the Physics of Living Cells, a Physics Frontiers Center at Illinois supported by the National Science Foundation, and the NASA Astrobiology Institute for Universal Biology at Illinois, which Goldenfeld directs. Goldenfeld and Xue embarked on this work because of their interest in transposons, small regions of DNA that can move themselves from one part of the genome to another during the lifetime of a cell -- a capability that has earned them the name "jumping genes." Collectively, various types of transposons make up almost half of the human genome. When they move around, they may create mutations in or alter the activity of a functional gene; transposons can therefore create new genetic profiles in a population for natural selection to act on, in either a positive or negative way. The Illinois researchers wanted to learn more about how evolution works on this level, the level of whole organisms, by looking at the metaphorical ecosystem of the human genome. In this view, the physical structure of the DNA that makes up the genome acts like an environment, in which two types of transposons, long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), have a competitive relationship with one another. In order to replicate, SINEs steal the molecular machinery that LINEs use to copy themselves, somewhat like a cuckoo bird tricks other birds into raising her chicks for her while abandoning their own. With help from Oleg Simakov, a researcher at the Okinawa Institute of Science and Technology, Xue and Goldenfeld focused on the biology of L1 elements and Alu elements, respectively common types of LINEs and SINEs in the human genome. The researchers adopted methods from modern statistical physics and modeled the interaction between Alu and L1 elements mathematically as a stochastic process -- a process created from chance interactions. This method has been successfully applied in ecology to describe predator-prey interactions; Xue and Goldenfeld simulated the movements of transposons within the human genome with the same mathematical method. Their models included a detailed accounting for how Alu elements steal the molecular machinery L1 elements use to copy themselves. Xue and Goldenfeld's results predicted that populations of LINE and SINE elements in the genome are expected to oscillate the way those of, for example, wolves and rabbits might. "We realized that the transposons' interaction actually was pretty much like the predator-prey interaction in ecology," said Xue. "We came up with the idea, why don't we apply the same idea of predator-prey dynamics . . .we expected to see the oscillations we see in the predator-prey model. So we first did the simulation and we saw the oscillations we expected, and we got really excited." In other words, too many SINEs and the LINEs start to suffer, and soon there are not enough for all the SINEs to exploit. SINEs start to suffer, and the LINEs make a come-back. Xue and Goldenfeld's model made the surprising prediction that these oscillations occur over a timescale that is longer than the human lifespan -- waves of Alu elements and L1 elements pushing and pulling at each other in slow motion across generations of the human genomes that carry them. "The most enlightening aspect of the study for me was the fact that we could really compute the timescales, and see that it is possible that we could observe these things," said Goldenfeld. "We have a prediction for what happens in single cells, and we may be able to actually do an experiment to observe these things, though the period is longer than the lifetime of a single cell." In a related study, Goldenfeld's laboratory has collaborated with the laboratory of fellow physicist and IGB Biocomplexity research theme member Thomas Kuhlman to visualize the movements of transposons within the genomes of living cells. Using this type of innovative technology, and by studying the history of molecular evolution in other species, Goldenfeld and Xue hope to test some of the predictions made by their model and continue to gain insight into the dynamic world of the genome.


News Article | November 14, 2016
Site: phys.org

The findings, published in Physical Review Letters by physicists Chi Xue and Nigel Goldenfeld, are an important step toward understanding the complex ways that genomes change over the lifetime of individual organisms, and how they evolve over generations. "These are genes that are active and are doing genome editing in real time in living cells, and this is a start of trying to really understand them in much more detail than has been done before," said Goldenfeld, who leads the Biocomplexity research theme at the Carl R. Woese Institute for Universal Biology (IGB). "This is helping us understand the evolution of complexity and the evolution of genomes." The study was supported by Center for the Physics of Living Cells, a Physics Frontiers Center at Illinois supported by the National Science Foundation, and the NASA Astrobiology Institute for Universal Biology at Illinois, which Goldenfeld directs. Goldenfeld and Xue embarked on this work because of their interest in transposons, small regions of DNA that can move themselves from one part of the genome to another during the lifetime of a cell—a capability that has earned them the name "jumping genes." Collectively, various types of transposons make up almost half of the human genome. When they move around, they may create mutations in or alter the activity of a functional gene; transposons can therefore create new genetic profiles in a population for natural selection to act on, in either a positive or negative way. The Illinois researchers wanted to learn more about how evolution works on this level, the level of whole organisms, by looking at the metaphorical ecosystem of the human genome. In this view, the physical structure of the DNA that makes up the genome acts like an environment, in which two types of transposons, long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), have a competitive relationship with one another. In order to replicate, SINEs steal the molecular machinery that LINEs use to copy themselves, somewhat like a cuckoo bird tricks other birds into raising her chicks for her while abandoning their own. With help from Oleg Simakov, a researcher at the Okinawa Institute of Science and Technology, Xue and Goldenfeld focused on the biology of L1 elements and Alu elements, respectively common types of LINEs and SINEs in the human genome. The researchers adopted methods from modern statistical physics and modeled the interaction between Alu and L1 elements mathematically as a stochastic process—a process created from chance interactions. This method has been successfully applied in ecology to describe predator-prey interactions; Xue and Goldenfeld simulated the movements of transposons within the human genome with the same mathematical method. Their models included a detailed accounting for how Alu elements steal the molecular machinery L1 elements use to copy themselves. Xue and Goldenfeld's results predicted that populations of LINE and SINE elements in the genome are expected to oscillate the way those of, for example, wolves and rabbits might. "We realized that the transposons' interaction actually was pretty much like the predator-prey interaction in ecology," said Xue. "We came up with the idea, why don't we apply the same idea of predator-prey dynamics . . .we expected to see the oscillations we see in the predator-prey model. So we first did the simulation and we saw the oscillations we expected, and we got really excited." In other words, too many SINEs and the LINEs start to suffer, and soon there are not enough for all the SINEs to exploit. SINEs start to suffer, and the LINEs make a come-back. Xue and Goldenfeld's model made the surprising prediction that these oscillations occur over a timescale that is longer than the human lifespan—waves of Alu elements and L1 elements pushing and pulling at each other in slow motion across generations of the human genomes that carry them. "The most enlightening aspect of the study for me was the fact that we could really compute the timescales, and see that it is possible that we could observe these things," said Goldenfeld. "We have a prediction for what happens in single cells, and we may be able to actually do an experiment to observe these things, though the period is longer than the lifetime of a single cell." In a related study, Goldenfeld's laboratory has collaborated with the laboratory of fellow physicist and IGB Biocomplexity research theme member Thomas Kuhlman to visualize the movements of transposons within the genomes of living cells. Using this type of innovative technology, and by studying the history of molecular evolution in other species, Goldenfeld and Xue hope to test some of the predictions made by their model and continue to gain insight into the dynamic world of the genome. More information: Chi Xue et al, Stochastic Predator-Prey Dynamics of Transposons in the Human Genome, Physical Review Letters (2016). DOI: 10.1103/PhysRevLett.117.208101


News Article | March 23, 2016
Site: phys.org

Led by Aleksei Aksimentiev, a professor of physics at the University of Illinois, and Taekjip Ha, a professor of biophysics and biophysical chemistry at Johns Hopkins University and an adjunct at the University of Illinois Center for the Physics of Living Cells along with Aksimentiev, the researchers published their work in the journal Nature Communications. "We are still only starting to explore the physical properties of DNA. It's not just a string of letters," Aksimentiev said. "It's a complex molecule with unique characteristics. The prevailing hypothesis is that everything that happens inside the nucleus, the way the DNA is organized, is all the work of proteins. What we show is that direct DNA-DNA interactions may play a role in large-scale chromosome organization as well." Using the Blue Waters supercomputer at the National Center for Supercomputing Applications on the Illinois campus, Aksimentiev and postdoctoral researcher Jejoong Yoo performed detailed simulations of two DNA molecules interacting in a charged solution such as is found in the cell. The supercomputer allowed them to map each individual atom and its behavior, and to measure the forces between the molecules. They found that, though DNA molecules tend to repel each other in water, in a cell-like environment two DNA molecules can interact according to their respective sequences. "In the DNA alphabet, there is A, T, G and C. We found that when a sequence is rich in A and T, there is a stronger attraction," Aksimentiev said. "Then we looked at what actually causes it at the molecular level. We like to think of DNA as a nice symmetrical helix, but actually there's a line of bumps which are methyl groups, which we find are the key to regulating this sequence-dependent attraction." One of the processes for regulating gene expression is methylation, which adds methyl groups to the DNA helix. In further simulations, the researchers found that the methyl groups strengthen the attraction, so sequences heavy in G and C with methyl groups attached will interact just as strongly as sequences rich in A and T. "The key is the presence of charged particles in the solution," Aksimentiev said. "Let's say you have two people who don't like each other, but I like them both, so I can shake hands with both of them and bring them close. The counter-ions work exactly like that. The strength of how they pull the DNA molecules together depends on how many of them are between the molecules. When we have these bumps, we have a lot of counter-ions." Ha and graduate researcher Hajin Kim experimentally verified the findings of the simulations. Using advanced single-molecule imaging techniques, they isolated two DNA molecules inside a tiny bubble, then watched to see how the molecules interacted. The experiments matched well with the data from the simulations, both for the sequence-dependent interactions and for interactions between methylated DNA. "It was wonderful to see the computational predictions borne out exactly in our experiments," Ha said. "It tells us how accurate the atomic-level simulations are and shows that they can guide new research avenues." The researchers posit that the observed interactions between DNA molecules could play a role in how chromosomes are organized in the cell and which ones are expanded or folded up compactly, determining functions of different cell types or regulating the cell cycle. "For example, once you methylate DNA, the chromosome becomes more compact. It prevents the cellular machinery from accessing the DNA," Aksimentiev said. "It's a way to tell which genes are turned on and which are turned off. This could be part of the bigger question of how chromosomes are arranged and how organizational mechanisms can affect gene expression." Explore further: Charged graphene gives DNA a stage to perform molecular gymnastics More information: Jejoong Yoo et al. Direct evidence for sequence-dependent attraction between double-stranded DNA controlled by methylation, Nature Communications (2016). DOI: 10.1038/ncomms11045

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