Chemists discover new way to organize DNA in single-celled organisms

It has only recently been discovered that single-celled organisms (bacteria and archaea) also have histones – proteins that make up DNA. Now, PhD student Samuel Schwab from Leiden University has found that histones in these organisms are much more diverse than previously thought.

Schwab and his colleagues describe more than 17 different groups, each with their own unique structure and function. Their findings are published in the journal Nature Communications.

“DNA is a very large molecule, so technically it can’t fit inside a cell,” explains Samuel Schwab, a PhD student in Dame’s group at the Leiden Institute of Chemistry, “so there are proteins that compact DNA; the best known are histones.”

For a long time, histones were thought to be found only in complex life forms, but scientists discovered them in archaea and eventually bacteria (both single-celled organisms without nuclei). Histones form tiny spheres called nucleosomes, around which DNA wraps.

Unravelling histones with the help of computational power

Archaeal and bacterial DNA appears to have many “recipes” that are very similar to those of known histones, but with subtle differences. “We really wanted to know what histones these recipes produce,” Schwab says.

“This is very difficult to do in a lab, but fortunately, three years ago a smart AI algorithm called AlphaFold was introduced. This program is very good at predicting protein structures based on their corresponding sequences (recipe) in DNA.”

From vast protein databases, Schwab has collected more than 6,000 DNA sequences that could serve as recipes for undiscovered histones from archaea and bacteria. “With the help of AlphaFold and the Leiden supercomputer facility ALICE, we predicted the structures of histones that correspond to all these sequences,” he says.

Archaeal and bacterial histones turned out to be much more diverse than previously thought: Schwab identified a total of 17 different groups, some of which were already known, but others with entirely new structures.

The researchers then tested whether the computer was right: “We determined the structure of one of these new groups of histones in the lab,” Schwab says, “and found that it was nearly exactly as the computer predicted.”

Not just wrapping, but folding and bridging too

Based on the predicted structures, the researchers were able to hypothesize how these proteins might behave and what they might do with DNA: “We found that there are not only spheres that wrap around DNA, but also other structures that can, for example, fold DNA or bridge different parts of the DNA strand to make loops,” Schwab says.

“What’s also interesting is the discovery that some histones bind to membranes but not to DNA,” adds supervisor Remus Dame, “which means that histones have functions other than organizing DNA. But this needs to be investigated further.”

The Dame Research Group’s work contributes to a better understanding of the evolution of DNA organization and how different organisms manage their genetic material. Dame says, “Furthermore, this knowledge helps us interpret DNA data and measurements. We still know very little about what actually happens inside the cell.”

“There is still a lot to learn about the role of these histones,” Schwab says. “The discovery of these new variants is just the beginning.”