An Unfolding Story

A model of chromatin explores how it folds and unfolds

To fit an organism’s DNA into a single cell, it has to be tightly compacted, first wound around proteins to form chromatin fibers, then further coiled into chromosomes. Computer simulations by scientists at New York University (NYU) have now provided a better understanding of how this folding occurs. The results appeared in the June 7 issue of the Proceedings of the National Academy of Sciences.


“It’s very important to understand how chromatin folds and unfolds,” says Tamar Schlick, PhD, professor of chemistry, mathematics, and computer science at New York University and senior author on the paper. Chromatin folding is directly involved in gene expression and silencing: chromatin— a complex of DNA and specialized proteins—must unwind so that the cellular machinery can access the DNA and begin copying or transcribing the genetic information into proteins.


A 12-nucleosome array adopts extended beads-on-a-string conformations in a low salt solution (outer ring), while it compacts at midlevel salt concentrations (middle ring) and folds into irregular zig-zag structures at high salt concentrations (inner ring). Courtesy of Tamar Schlick.A stretched-out chromatin fiber looks like “beads on a string.” The DNA is wound around repeating 8-protein complexes at approximately regular intervals; each DNA/protein “bead” is called a nucleosome. Scientists already knew that chromatin unfolds in low-salt solutions and folds in high-salt solutions, such as found in cells. But they couldn’t distinguish between four possible folding structures (perpendicular and parallel zig-zag, and perpendicular and parallel solenoid), until now.


The scientists at NYU modeled the folding of a 12-nucleosome fragment of chromatin using what they believe is the highest-resolution simulation of chromatin folding to date. Chromatin is too large and complex to model atom- by-atom with today’s computing power. But modeling at the level of macromolecules (proteins and DNA) is too crude to give a realistic picture. So, NYU scientists compromised: Using structural experimental information about each nucleosome and the electrostatic forces associated with each atom, they built a realistic mechanical model containing essential features of the system while approximating others. They modeled the key positive and negative charges found on the amino acids and nucleotides, without explicitly modeling every atom. Chromatin folds according to the attraction and repulsion of these charged particles with each other and with the salt solution.


“This allows us to do long-time simulations of the complex system using what is a very realistic model of what the nucleosome core would look like.” Schlick says.


Regardless of which of the four folding models they started their simulation with, they found that their virtual chromatin always folded into an irregular zig-zag conformation after enough computational steps. They also pinpointed the key electrostatic attractions and repulsions that drive chromatin folding and unfolding.


“This is not the first attempt to model the chromatin fiber, but this one makes the fewest artificial assumptions,” says Sergei Grigoryev, PhD, assistant professor of biochemistry and molecular biology at Penn State University College of Medicine.


Their findings agree with the experimental data he has collected on chromatin folding using electron microscopy.


“I really admire their paper,” he says. “For the first time it produced a nucleosome array model that really matches biological observations.”

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