The death of genes

Apr 10, 2014

Dr. Yun Li

Credit: Delaware Valley College. Dr. Yun Li, a DelVal chemistry faculty member, published research in the Journal of Physical Chemistry, which helps with understanding the death of undesirable genes.

If you took the ribbon from a cassette tape and compressed it, you wouldn’t be able to hear the music. Similarly, if you soften DNA and wrap it into a compact bundle, you can silence genes, explained Dr. Yun Li, a chemistry faculty member at Delaware Valley College who is researching this process.

Working with colleagues from Rutgers University, Dr. Li has been examining a method that softens DNA, which allows it to be compressed like the cassette tape’s ribbon. The softening is created by adding an extra group, called a methyl group, to the fifth place on the ring that makes up cytosine, one of the building blocks of DNA. Understanding how to cause this softening can help scientists with figuring out how to “turn off” undesirable genes, such as retroviruses like HIV, which have permanently embedded themselves into the host’s genome.

“I’m very proud to have been part of this project,” said Dr. Li. “I think it is something that will be incorporated into textbooks in the future and I’m glad to have my name associated with it.”

With drugs to treat cancer and other issues, Dr. Li, said the emphasis has traditionally been on drugs that target proteins.

“That makes DNA a treasure chest,” said Dr. Li . “Controlled DNA silencing through methylation has great medical potential. It can lead to the development of a different kind of gene therapy. It might even help with tissue regeneration, thus helping people who suffered from spinal cord injuries.”

In a paper published by The Journal of Physical Chemistry, “5-Methylation of Cytosine in CG:CG Base-Pair Steps: A Physiochemical Mechanism for the Epigenetic Control of DNA Nanomechanics,” the team describes how making a small change to cytosine, one of the building blocks of DNA, leads to this softening and what that means for DNA mechanics.

If DNA were a spiral staircase, cytosine would be one-half of a step. It pairs with guanine, in what is called a CG:CG base-pair step, which looks like one step on the staircase.

Dr. Li worked with two colleagues in his field, Tahir I. Yusufaly and Dr. Wilma K. Olson, to look at what happens when you manipulate one of those half steps.

Cytosine is shaped like a ring, with branches coming off it. Using a computer program, the team added a methyl group, three hydrogen atoms bonded to a carbon atom, to the fifth location on that ring that normally just contains a hydrogen atom.

They are studying how 5-methylation, altering the cytosine by adding a piece in the fifth place on its ring, alters DNA structure. The work has implications for cancer research and stem cell research.


5-methylation diagram
Credit: Dr. Yun Li. In the line figure above, point A represents a methyl group, attached to the cytosine through point B; point D represents all other atoms in the base-pair step, attached to the same cytosine through point C. Computer simulation shows that the introduction of a methyl group (enclosed in the red circle) to cytosine significantly increases the oscillation hinged at point C, in other words, cytosine 5-methylation locally softens DNA.

5-Methylation is a unique mechanism in gene deactivation – the methylation pattern of a cell’s DNA is passed on to its children cells. Thus, methylation patterns are used to prevent a cell from digressing into a less differentiated cell type. If you alter the pattern you can change a cell’s type. If you remove it completely you get a stem cell.

“If we can understand more of DNA methylation, we can create drugs that can silence genes in a very specific fashion,” said Dr. Li. “Currently most drugs target proteins. It’s certainly something to think about and as we’re more and more capable of doing so, it will open up a new arena to combat disease.”

He said the work he’s a part of is very theoretical, but it does tell us why the methylation of cytosine could silence genes.

DNA naturally resists being packed together, crumpled or tangled. By making the small change to cytosine, introducing the extra group to its ring, it makes DNA softer-more easily squeezed together.

“If we want to silence a gene that shouldn’t be expressed we need to make DNA softer,” said Dr. Li, who started working on the project eight years ago as a graduate student at Rutgers.

He will be continuing the work and will be publishing a follow-up paper on another aspect of DNA.

The research uses computer software, which simulates the changes. Dr. Li provided the DNA vibration patterns for the computer simulation by analyzing the structural variations in a set of carefully chosen protein-DNA complexes. Tahir, a Rutgers graduate student, subsequently added the methyl group to the cytosine and studied how these vibration patterns are changed in computer simulations.

In order to provide the real data, Dr. Li had to look at a large number of DNA binding proteins. This makes the motion used in the simulation real.

CG pairs are rigid while AT pairs are soft. They found that adding the extra group on the fifth place could soften CG pairs.

Methylation of the cytosine makes the DNA sequence more homogenous and makes it easier to condense DNA-which helped the team with better understanding the death of DNA.

Dr. Li used a protein database to pull in data and then, wrote computer software to sort the data, to make sure it was not biased to one particular protein family.

“It was very much humans and computers working together; the data was hand-picked with the help of the computer,” said Dr. Li.

He would like to see more involvement of the undergraduate students at the College in this type of research, but said it can be difficult for students.

“Some students could get involved with this type of research, but it’s not easy,” said Dr. Li. “If I see students with interest I would be happy to include them.”

He is introducing his advanced students to some of the computer programs he used in the research.

“The program that generated this graph is used in Advanced Biochemistry,” said Dr. Li, pointing to DNA graph on Page 5. “I show the students how to use the program and interpret results.”

He learned computer software design as a graduate student, and would encourage students who want to do similar work to learn as much as they can about it.

He said the fight against health issues related to genes is interdisciplinary and that it’s an area where biologists, chemists, computer scientists and mathematicians can come together to solve a problem.