A research team has made significant discoveries regarding the processes that occur in the moments and hours following cell division. This advancement enhances our comprehension of human biology, which could pave the way for developing more effective medications.
DNA replication occurs constantly throughout the human body, taking place trillions of times each day. Each time a cell divides—whether to mend injured tissue, replace aging cells, or facilitate growth—DNA is replicated to ensure that the new cells retain the same genetic information.
Despite its crucial role in human biology, the intricacies of DNA replication have not been well understood. This is largely due to the challenges scientists face in directly observing this complex process. Previous attempts to study replication were hindered by the use of chemicals that could harm DNA or methods that could only capture brief segments of DNA, leading to incomplete insights.
A recent study published in Cell by researchers at Gladstone Institutes has made strides in addressing these challenges by introducing a novel approach that combines long-read DNA sequencing with a predictive artificial intelligence model. This innovation provides a clearer understanding of the events that unfold shortly after DNA is replicated.
“This has been a persistent biochemical question,” explains Gladstone Investigator Vijay Ramani, PhD, the study’s lead author. “The replication machinery actually dismantles existing DNA structures, which must then be accurately restored in the newly formed cells. To comprehend how this restoration occurs, we needed a fresh method to map DNA structure both prior to and following replication.”
More Vulnerable Than We Knew
Ramani is pioneering advancements in a field known as single-cell genomics, which aims to explore genome activity at the individual cell and molecular level. He and his colleagues have created numerous innovative techniques for better understanding the molecular processes that influence health and contribute to diseases.
In this latest study, the researchers introduced a technique called RASAM, which stands for “replication-aware single-molecule accessibility mapping.” This innovative tool has led to an unexpected finding: large regions of newly synthesized DNA remain “hyperaccessible” for several hours, indicating that other proteins, including those involved in gene regulation, can easily access this DNA.
“We might have assumed this level of accessibility could lead to genomic chaos, but that’s not the case,” Ramani remarks.
In contrast to mature DNA that is tightly packed into structures known as nucleosomes, the research team observed that nascent DNA is only partially wrapped and remains in a “loose” state for several hours after replication.
“The observation of this phenomenon is entirely novel,” states Ramani. “It has significant ramifications for our fundamental understanding of biology and could also enhance the development of new treatments for various diseases.”
For instance, in cancer, characterized by rapid cell division, medications could target cells during this temporary accessible phase following replication, potentially destroying them. Alternatively, researchers might harness this period of DNA accessibility to modify gene expression in a manner that helps avert disease.
Now You See It
In their experiments, Ramani and his team—including lead authors Megan Ostrowski, a research associate in the Ramani Lab, and Marty Yang, PhD, a bioinformatics fellow—provided evidence that this heightened accessibility is controlled at specific areas on DNA strands where gene expression initiates.
Nevertheless, many questions remain, and new inquiries surfaced during the research process, especially concerning the protective mechanisms of newly formed cells. These present exciting new research opportunities for Ramani.
“What excites me about this research is how it revolves around the methodologies that enable discovery,” Ramani shares. “For biologists, our observations dictate our understanding. The accuracy of our measurements is crucial for devising treatments and making informed decisions regarding diseases. This is precisely why these new methods and tools are invaluable. We can now examine genomic regions previously hidden from view.”
