A new study led by researchers at the University of California, San Diego, has uncovered a new mechanism by which DNA unfolds to initiate gene transcription. The molecular mechanism, termed “induced unwrapping,” reveals how DNA, which is normally tightly wrapped around proteins called histones to form chromatin, can be progressively unwrapped to allow access by transcription machinery to the genes that code for proteins.

The research team, led by Andrei Chavan, PhD, a former postdoctoral researcher in the laboratory of Shelley L. Berger, PhD, distinguished professor in the Department of Chemistry and Biochemistry at UC San Diego, combined single-molecule experiments and computational simulations to investigate how the ATP-dependent chromatin remodeler ACF (ATP-utilizing chromatin assembly and remodeling factor) unwraps DNA.

DNA is the molecule that carries the instructions for an organism’s development and characteristics, but its long, string-like structure needs to be organized and packaged within cells to fit inside the nucleus. To do this, DNA is wrapped around histones to form “nucleosomes,” which are the fundamental units of chromatin.

When a gene needs to be transcribed (the first step of gene expression), the DNA must be unwrapped from the histones so that transcription machinery can access it. Previously, researchers thought that DNA unwrapping occurred through the forceful eviction of histones, a process known as nucleosome disassembly.

However, the new study reveals an alternative mechanism, induced unwrapping, which involves the progressive unwrapping of DNA from histones without complete nucleosome disassembly.

“We found that ACF binding alone can cause DNA to start unwrapping, and this opening up of the DNA facilitates transcription initiation,” said Chavan, now a postdoctoral researcher at the Stowers Institute for Medical Research in Kansas City, Missouri.

The researchers used single-molecule experiments to precisely measure how DNA unwinds from the nucleosome before and after ACF binding, and their results showed that ACF could cause DNA to unwrap by about 1.75 turns around the histone octamer.

“Our simulations supported and expanded upon the experimental findings, allowing us to visualize how ACF initially recognizes and binds to the nucleosome, and how it begins the process of DNA unwrapping,” said co-author Olga Popa, PhD, a former postdoctoral researcher in the Berger laboratory and now an assistant professor of Physics and Integrative STEM Education at MiraCosta College in Oceanside, California.

The work not only identifies induced unwrapping as a distinct mechanism of DNA unwinding but also sheds light on how other enzymes might unfold DNA to regulate gene expression. Gene dysregulation is associated with numerous diseases, including cancer, and understanding the mechanisms by which DNA is organized and accessed is a critical step toward developing therapies to restore normal gene expression patterns.

“ACF-induced DNA unwrapping is an important new concept in chromatin biology, providing a revised view of how remodeling complexes access DNA for gene regulation,” said Berger. “The research not only enriches our fundamental understanding of gene expression but also identifies potential new targets for therapeutic intervention in diseases resulting from aberrant gene regulation.”