Research shows how bacteria silence potentially deadly genes

Humans are all made of collections of cells, where each cell contains instructions in the DNA to become another cell. The factor that differentiates a skin cell from a heart cell from a brain cell is the expression or silencing of genes.

Polyphosphate during liquid-liquid phase separation formation. Image Credit: Joseph Basalla, Ursula Jakob and Anthony Vecchiarelli.

Earlier, this process was believed to occur only in animals, plants, and other living organisms that have cells with a nucleus—called eukaryotes. A recent study by U-M researchers, published in the journal Science Advances, extends further support to the emerging belief that bacteria also use genetic silencing to safeguard themselves against deadly mutations.

For a very long time, bacterial chromosomes were thought to be fully expressed, with no control with regard to chromosome accessibility. That view has changed dramatically.”

Ursula Jakob PhD, Study Senior Author and Professor, Molecular, Cellular and Developmental Biology and Biological Chemistry, Michigan Medicine, University of Michigan

In eukaryotes, histones, a protein type, facilitate control over the activated genes. Until recently, these proteins were believed to be absent in bacteria. However, scientists, along with Jakob’s U-M associate Peter Freddolino, associate professor of biological chemistry and computational medicine and bioinformatics, have confirmed that bacteria do control the expression of genes.

The types of elements that are silenced are some of the same things that get silenced by heterochromatin in eukaryotes: mobile, problematic genetic element.”

Peter Freddolino PhD, Associate Professor, Biological Chemistry, Computational Medicine, and Bioinformatics, Michigan Medicine, University of Michigan

Heterochromatin, a tightly packed DNA bundle, supports the chromosome and regulates gene expression.

Furthermore, as in animal cells, which can go through altered gene expression during stress, bacteria comprise genetic sequences that can turn to be problematic. For instance, bacteria can get infected with viruses that mix into their genomes and become genetic elements known as prophages. In specific conditions, these prophages can result in the death of the bacterial cell. For the survival of the cell, identifying and silencing these regions are crucial.

The recent study carried out by the team shows how bacteria do this—with an ancient molecule found wherever there is life, known as polyphosphate. Jakob says that the molecule was so crucial that Arthur Kornberg, a Noble Prize winner, studied it for the last 20 years of his career.

“He found it plays a role in bacteria, in virulence, in stress responses, but could never figure out what exactly it was doing,” added Jakob.

Jakob, Freddolino, and their team discovered that this simple molecule targets a nucleoid-associated protein to the regions where the bacterial genome has these tricky elements and suppresses their transcription.

Jakob added that when the polyphosphate or the nucleoid-associated protein was removed, it resulted in the immediate mobilization of these prophages by the bacteria, eventually leading to significant mutations.

“The bacteria can die very easily under those circumstances. It’s an extremely important system that had not been appreciated until now,” says Freddolino.

Also, researchers have shown that in vitro, polyphosphate, the nucleoid-associated protein, and DNA form droplets in a method called liquid–liquid phase separation—a process that also underlies the arrangement of compartments outside the nucleus found in cells of eukaryotes.

This discovery continues to push the idea we now have that bacteria behave in very similar ways to eukaryotes in the way in which they organize their chromosomes.”

Peter Freddolino PhD, Associate Professor, Biological Chemistry, Computational Medicine, and Bioinformatics, Michigan Medicine, University of Michigan

He concluded that by utilizing this silencing process, scientists can reverse it which eventually opens up new avenues for antibiotics.