New Imaging Technique Overturns Longstanding Model of DNA Folding

How can 6½ feet of DNA be folded into the tiny nucleus of a cell? Researchers funded by NIH have developed a new imaging method that visualizes a very different DNA structure, featuring small folds of DNA in close proximity. The study reveals that the DNA-protein structure, known as chromatin, is a much more diverse and flexible chain than previously thought. This provides exciting new insights into how chromatin directs a nimbler interaction between different genes to regulate gene expression and provides a mechanism for chemical modifications of DNA to be maintained as cells divide. The results were featured in the July 28 issue of Science.

 

For decades, experiments suggested a hierarchical folding model in which DNA segments spooled around 11 nanometer-sized protein particles assembled into rigid fibers that folded into larger and larger loops to form chromosomes. However, that model was based on structures of chromatin in vitro after harsh chemical extraction of cellular components.

 

Now, researchers at the Salk Institute, La Jolla, Calif., funded by the NIH Common Fund, have developed an electron microscopy technique called ChromEMT that enables the 3-D structure and packing of DNA to be visualized inside the cell nucleus of intact cells. 

 

Contrary to the longstanding textbook models, DNA forms flexible chromatin chains that have fluctuating diameters between 5 and 24 nanometers that collapse and pack together in a wide range of configurations and concentrations.

 

The newly observed and diverse array of structures provides for a more flexible human genome that can bend at varying lengths and rapidly collapse into chromosomes at cell division. It explains how variations in DNA sequences and interactions could result in different structures that exquisitely fine tune the activity and expression of genes.

 

“This is groundbreaking work that will change the genetics and biochemistry textbooks,” said Dr. Roderic Pettigrew, director of NIBIB, which administered the grant. “It’s an outstanding example of how constantly improving imaging techniques continue to show the true structure of everything from neuronal connections in the brain to the correct visualization of gene expression in the cell. It reveals how these complex biological structures are able to perform the myriad intricate and elaborate functions of the human body.”