Each human cell contains an incredible 1.8 meters of DNA. Cells have evolved not only to fit all that genetic material inside each tiny cell, but also to cram it into an even smaller container within the cell—the nucleus. This astonishing feat is accomplished by winding DNA around spool-shaped proteins called histones. Once packaged, the histone-DNA complex, called chromatin, has undergone a staggering 20,000-fold reduction in overall length.
However, chromatin has another exceedingly important task that goes beyond its packaging duties. The histone-DNA complex is a dynamic structure that can regulate which genes are active at any given moment by unwinding that specific region of packed DNA. Conversely, cells can repress genes by forming compact and dense chromatin fibers—achieved through effector proteins that attach to chromatin and change their 3D structure to either an open or compact state.
The interaction between effector proteins and DNA has eluded scientists for many years, due in large part to the complex’s weak binding affinity. However, researchers at the Swiss Federal Institute of Technology in Lausanne (EPFL) have taken great strides to tracking these interactions one molecule at a time. In a new study, EPFL researchers have observed how a major effector protein speeds up its search for chromatin binding sites by pairing up with others of its kind.
“We want to observe complex biology as it happens, and understand it on a quantitative level,” stated Beat Fierz, Ph.D., assistant professor of biophysical chemistry at the EPFL and senior author of the study. “Our chemical methods give us complete control over protein-chromatin dynamics, and the current study sets the stage for such unprecedented insights.”
The findings from this study were published online today in Nature Communications through an article entitled “Multivalency governs HP1α association dynamics with the silent chromatin state.”
Dr. Fierz and his colleagues studied an effector protein called HP1α that dissociates from chromatin fairly easily—an uncommon trait among DNA-binding proteins. The researchers discovered that to compensate for its weak DNA affinity, HP1α has a more rapid binding rate and dimerizes to maximize binding efficiency.
The investigators used single-molecule measurements, which allowed them to observe individual HP1α proteins interacting with chromatin in real time. Additionally, the EPFL team synthesized chromatin fibers that contained the appropriate chemical identifiers and used this system to explore HP1α binding under different conditions and experimental parameters.
Together with the increase in binding rate, the scientists also found that when HP1α proteins connect with each other to make dimers, they increase the total number of possible binding sites, maximizing the interaction with chromatin. By amplifying its binding speed and multiplying its binding sites, HP1α has a better chance of holding onto chromatin longer, thus regulating gene expression.
“This effect results from increased avidity together with strengthened nonspecific chromatin interactions of dimeric HP1a,” the scientists explained. “We propose that accelerated chromatin binding is a key feature of effector multivalency, allowing for fast and efficient competition for binding sites in the crowded nuclear compartment.”