Chromatin Fiber: Zigzag or Solenoid?

Try packing a two-meter-long stretch of DNA into a cell nucleus just a few millionths of a meter thick—with key coding segments readily accessible. It’s a seemingly impossible feat that eukaryotic cells routinely pull off by building a highly compact, fibrous mix of DNA and proteins called chromatin. Now a new study uses a combination of novel lab experiments and computer simulations to provide long-sought details about the structure of chromatin fibers.

 

Chromatin packing gets denser with the addition of linker histones (LH) and divalent ions (Mg) in this computational simulation (A-C) . In the close-ups at right, the cores of alternate nucleosomes have different coloring (white or blue) with red linkers for better visualization. The zigzag structure dominates at low ionic concentrations (D) but in the presence of magnesium chloride, several nucleosomes have bent linkers and the nucleosomes interact in more of a solenoid arrangement (E). Reprinted from Grigoryev, S, et al., Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions, Proceedings of the National Academy of Sciences, 106: 32:13317-13322 (2009).

“Our study appears to resolve a 30-year-old controversy about the structure of chromatin fiber,” says Gaurav Arya, PhD, assistant professor of nanoengineering at the University of California, San Diego. The findings, published in the August 11 issue of Proceedings of the National Academy of Sciences, could improve our understanding of cell growth, differentiation, and cancer.

 

This much is generally accepted: Chromatin starts off as a series of nucleosomes—protein spindles wrapped with about a turn and a half of DNA—connected by stretches of linker DNA; this “beads on a string” structure then folds itself into stiff, compact fibers.

 

What is debated is the interaction and arrangement of nucleosomes within this fiber. One school of thought favors a spiral arrangement, or solenoid, in which successive nucleosomes interact and are connected with bent DNA linkers. Another school argues that DNA is too stiff to bend easily, and proposes instead a zigzag structure with straight linkers in which alternate nucleosomes interact. Until now, this issue could not be resolved because the available experimental techniques required the chromatin fiber to be unwrapped before it could be studied.

 

In the new work, researchers first used formaldehyde to create permanent cross-links between interacting nucleosomes. These interactions give rise to loops in the fiber when it is unwrapped under various conditions. Studying these loops under an electron microscope, the researchers found evidence to support the existence of the zigzag structure in the absence of divalent ions such as magnesium; in the presence of such ions, however, a fraction of nucleosomes switch to the solenoid motif.

 

The researchers then used a computational model developed by New York University researcher Tamar Schlick, PhD, to simulate the structure of chromatin fiber. The model confirmed the experimental results and added additional details: Without divalent ions present, the zigzag fiber packs about 7 nucleosomes per 11nm stretch; with divalent ions, about 20 percent of the linkers in the fiber bend, solenoid-style, and this helps the fiber accommodate about 8 nucleosomes per 11nm.

 

“These results show that both the zigzag and solenoid topologies may be simultaneously present in chromatin fiber,” says the study’s lead experimentalist, Sergei Grigoryev, PhD, associate professor of biochemistry and molecular biology at Pennsylvania State University. “It’s very exciting that we could show this using both computational and experimental techniques.”

 

University of Wyoming molecular biologist Jordanka Zlatanova, PhD, who has been studying chromatin for more than 30 years, says the paper is an important contribution “because finally we seem to really understand what the chromatin fiber structure is.” It’s also a major advance experimentally, she says, because it captures nucleosome interactions under physiological conditions. Further, no other group has been able to come up with a computational model that fits the native structure of chromatin so well, she says.



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