Over the past 60 years, scientists have been able to observe how and when genetic information is replicated, identifying the existence of a "chronological order of replication," a process that controls when and in what order segments of DNA are replicated . However, scientists still cannot explain why such a specific chronological order exists. In a study published today, Dr. David Gilbert and his team have answered this question that has puzzled scientists for 60 years.
"Why do cells 'care' about the order in which they replicate their DNA?" asked lead scientist Dr. Gilbert. "After all -- all cells need to replicate all of their DNA. Our hypothesis has always been that it's not just DNA that replicates, but also all the regulatory molecules that read DNA." Dr. Gilbert further hypothesized that replication timing and There may be a purpose behind the process, because "Mother Nature doesn't waste this opportunity to control how DNA is read".
"The timing of your replication provides an ideal time to choose whether to maintain all of the regulators, continue the same functional interpretation of the information in the DNA, or change it to cause a new function," explains Dr. Gilbert.
Over the past 13 years, Dr. Gilbert and his team have shown that each type of cell has a unique chronological order of replication, and that diseased cells have marked changes in that order. In this study, Dr. Gilbert and his team investigated how changes in the "chronological order of replication" affect the packaging of DNA and its regulators, collectively known as the epigenome. The epigenome is the regulatory factor thought to control the "identity" of a cell, and the functions the cell will perform.
By eliminating a protein called RIF1, which helps regulate DNA replication, they found that the order of replication, sometimes almost completely, disappears, so that all segments of chromosomes are replicated at different times in different cells. Without RIF1, if cells were prevented from replicating their DNA, their epigenome would be fine. However, once DNA begins to replicate, DNA-associated regulatory molecules are erroneously incorporated and deteriorate with each round of DNA replication. Ultimately, the three-dimensional folding of chromosomes is also altered.
Dr. Gilbert believes that when the epigenome is disrupted by changing the timing of replication, cells may no longer perform their normal functions, or they may perform inappropriate functions. These inappropriate functions can have a huge negative impact on a person's health.
Dr Gilbert said: "We and others have previously shown that this order is altered in many diseases. Our laboratory has recently shown specific temporal alteration patterns that are statistically associated with poor outcomes in pediatric leukemia, In another study, it was associated with progeria disease."
Thus, the replication chronological scheme provides an entirely new stream of molecular pathways and biomarkers that lead to and identify disease states. This could lead to earlier diagnosis and more accurate prognosis for patients.
While Dr. Gilbert's work has answered an important question, he does not intend to stop here. "We believe that the epigenome ... is not only critical for a cell to maintain its identity, but we hypothesize that it is critical for cells to become other cell types."
Testing this hypothesis has implications for stem cell research and therapeutic applications of stem cells. important. Dr. Gilbert is currently using human stem cells to test how disruptions in replication timing affect the development of these cells into liver cells, heart cells and neurons. The results of this study will provide valuable information for future research on human health and disease.
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