DNA molecules directly interact with each other based on sequence

Liz Ahlberg, Illinois News Bureau
3/23/2016 9:22 AM

Illinois postdoctoral researcher Jejoong Yoo, left, and professor Aleksei Aksimentiev found that molecules of DNA directly interact with each other based on their sequences. Photo by L. Brian Stauffer
Illinois postdoctoral researcher Jejoong Yoo, left, and professor Aleksei Aksimentiev found that molecules of DNA directly interact with each other based on their sequences. Photo by L. Brian Stauffer
Proteins play a large role in DNA regulation, but a new study finds that DNA molecules directly interact with one another in a way that's dependent on the sequence of the DNA and epigenetic factors. This could have implications for how DNA is organized in the cell and even how genes are regulated in different cell types, the researchers say.

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 used atomic-level simulations to measure the forces between each atom. Image courtesy of Alek Aksimentiev, University of Illinois
The researchers used atomic-level simulations to measure the forces between each atom. Image courtesy of Alek Aksimentiev, University of Illinois
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."

"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."

 

Recent News

  • Accolades
  • Alumni News

Congratulations to Physics Illinois alumnus M. George Craford on being presented today with the IEEE Edison Medal of the Institute of Electrical and Electronics Engineers. The medal is awarded annually in recognition of a career of meritorious achievement in electrical science, electrical engineering, or the electrical arts. The citation reads, “for a lifetime of pioneering contributions to the development and commercialization of visible LED materials and devices.”

 

Craford is best known for his invention of the first yellow light emitting diode (LED). During his career, he developed and commercialized the technologies yielding the highest-brightness yellow, amber, and red LEDs as well as world-class blue LEDs. He is a pioneer whose contributions to his field are lasting.

  • Research

While heritable genetic mutations can alter phenotypic traits and enable populations to adapt to their environment, adaptation is frequently limited by trade-offs: a mutation advantageous to one trait might be detrimental to another.

Because of the interplay between the selection pressures present in complex environments and the trade-offs constraining phenotypes, predicting evolutionary dynamics is difficult.

Researchers at the University of Illinois at Urbana-Champaign have shown how evolutionary dynamics proceed when selection acts on two traits governed by a trade-off. The results move the life sciences a step closer to understanding the full complexity of evolution at the cellular level.

  • Research
  • Condensed Matter Physics

Since the discovery two decades ago of the unconventional topological superconductor Sr2RuO4, scientists have extensively investigated its properties at temperatures below its 1 K critical temperature (Tc), at which a phase transition from a metal to a superconducting state occurs. Now experiments done at the University of Illinois at Urbana-Champaign in the Madhavan and Abbamonte laboratories, in collaboration with researchers at six institutions in the U.S., Canada, United Kingdom, and Japan, have shed new light on the electronic properties of this material at temperatures 4 K above Tc. The team’s findings may elucidate yet-unresolved questions about Sr2RuO4’s emergent properties in the superconducting state.

  • Research
  • AMO/Quantum Physics

Using an atomic quantum simulator, scientists at the University of Illinois at Urbana-Champaign have achieved the first-ever direct observation of chiral currents in the model topological insulator, the 2-D integer quantum Hall system.

Topological Insulators (TIs) are arguably the most promising class of materials discovered in recent years, with many potential applications theorized. That’s because TIs exhibit a special quality: the surface of the material conducts electricity, while the bulk acts as an insulator. Over the last decade, scientists have extensively probed the microscopic properties of TIs, to better understand the fundamental physics that govern their peculiar behavior.

Atomic quantum simulation has proven an important tool for probing the characteristics of TIs, because it allows researchers greater control and greater possibilities for exploring regimes not currently accessible in real materials. Finely tuned laser beams are used to trap ultracold rubidium atoms (about a billion times colder than room temperature) in a lattice structure that precisely simulates the structure of ideal materials.