Harvard scientists have unraveled the inner architecture of bacterial genomes in a breakthrough discovery that may shed light on how chromosomes organize within a cell.

The findings came after researchers applied a new visualization technique that generated the first fluorescence super-resolution images of chromosomes within a single bacterial cell.

The work demonstrates “the massive potential provided by the combination of emerging super-resolution microscopy and clever biochemistry,” wrote Stefan W. Hell, director at the Max Planck Institute for Biophysical Chemistry, in an emailed statement. He added that the findings “open a new chapter in the study of bacteria molecular organization.”

The findings provide the first detailed picture of a class of DNA-interacting proteins called nucleoid-associated proteins (NAPs). This close-up look helped scientists determine their role in organizing chromosomes in bacteria, according to Xiaoliang Sunney Xie, a Harvard professor of chemistry and chemical biology and senior author of the study.

“This has given us a new view to the microscopic world of bacteria,” he said.

The research team—led by affiliates from the departments of chemistry, biology, and physics—used super-resolution images in combination with biochemical tests to study the bacterial genome. They found that HNS, a specific type of NAP, caused clusters to form within chromosomes, suggesting its role as a regulator of chromosome organization in bacteria.

“Before their work, the idea was that the chromosome didn’t have any particular organization,” said biology professor Richard M. Losick.

According to the researchers, the most significant challenge was finding an optimal method to visualize the sub-cellular genome within a single bacterium.

The inner contents enclosed by a single bacterium are difficult to image because bacterial cells, typically 100 times smaller than human cells, cannot be clearly seen using a common light microscope. Alternative approaches like electron microscopy, while able to clearly visualize sub-cellular matter, do not allow for the imaging of live cells.

“Our understanding of the cell biology of bacteria is ironically lagging behind that of mammalian cells due to the lack of imaging tools,” said Xiaowei Zhuang, a joint professor of chemistry and physics and senior author of the study.

To overcome this challenge, the researchers used an imaging technique called Stochastic Reconstruction Optical Microscopy (STORM), developed by the Zhuang laboratory.

The technology previously shed light on the inner workings of sub-cellular matter ranging from mitochondria to brain synapses.

“We hope to even further improve [STORM] resolution to better elucidate these interesting molecular processes,” Zhuang said.

The study was published in a recent issue of the journal “Science.”

—Staff writer Amy Guan can be reached at guan@fas.harvard.edu.