Researchers announced an important discovery Monday about the structure of human genetic material, an advance that one day could enable scientists to fix genetic defects that lead to disease.
Writing in the journal Proceedings of the National Academy of Sciences, the authors, who included experts from Stanford University, the Broad Institute of MIT and Harvard, described the process through which the 6-foot-long string of human DNA folds and organizes itself to fit within the microscopic confines of a cell nucleus.
Genetic mutations can lead to errors in DNA folding that have been linked with certain diseases, including some types of cancer. If confirmed, the discovery could have far-reaching implications, enabling scientists to understand how genes are turned on and off in different cells, and potentially to correct errors in DNA folding.
“It’s one of these simple questions that you think we would know the answer to, but actually we really don’t,” said Tom Misteli of the National Cancer Institute, an internationally renowned pioneer in the field of genome cell biology who was not involved in the research. “But I think the value of this paper is really in generating the hypothesis that can now be tested.”
The research team, led by Erez Aiden at the Baylor College of Medicine’s Center for Genome Architecture, described how certain codes within the DNA sequence lead to the formation of some 10,000 loops in the DNA. The loops connect the genes with switches that turn them on and off. Without the loops, the genes and switches would be separated by large swaths of DNA code.
The researchers tested their theory by creating a computer simulation using only the codes to tell the computer where to form the loops in the DNA. The computer-generated loops formed in the same way as loops found in human cells, and the researchers could predict from the genome sequence where those loops would form. Moreover, when the researchers used genome editing techniques to change the location of the codes, they could reorganize the loops exactly as they intended.
“We were able to use our insights into how loops form in nature in order to engineer genome loops artificially,” Aiden said. “That means that it is possible, at least in principle, to fix errors in genome folding by modifying a handful of genetic letters without disturbing the surrounding DNA.”
Misteli said the researchers’ work would have to be confirmed by other scientists before it is widely accepted. The next steps will include proving that the folding and organization is indeed linked to the way cells function.
“There’s more and more evidence that how the genome is organized inside the nucleus is relevant to disease,” he said. “If there are defects in organization mainly due to misregulation of genes and disease, understanding the basic mechanism will allow us to address that question.”
Suhas Rao, one of the two co-authors working as graduate students in Aiden’s lab, pointed to the example of Beckwith-Wiedemann syndrome, a condition linked to mutations in a pair of genes. The mutations cause infants to grow abnormally large.
“The mutation that occurs is a mutation that disrupts a loop anchor,” Rao sad. “And in the disease state, you’re missing a loop or you get a loop where you’re not supposed to.”
By manipulating the genome to refold the loops, scientists may be able to determine whether the incorrect folding is truly causing the disease and potentially have a way to fix it.
Aiden cautioned that such genome fixes are likely decades away and that much basic science work remains to be done.
“I don’t know when this is going to cure a disease in humans; I hope that someday these kinds of ideas could,” he said, noting that the process would be attempted in mice long before its use in humans.
Aiden completed a joint Ph.D. program at Harvard University and the Massachusetts Institute of Technology, where he developed a method of identifying loops in the genome. He was recruited to Baylor College of Medicine in 2013 to launch the Center for Genome Architecture, which studies the way the genome is formed in 3-D, and joined the Center for Theoretical Biological Physics at Rice University. He was a recipient of the Presidential Early Career Award for Scientists and Engineers in 2011.
Aiden’s team drew much attention in the field of genomic research last year when it accurately mapped all of the loops in the genome, a project scientists had been working on for the better part of a decade. Now they’ve taken the next huge step, from mapping to explaining how loops form, in less than a year.
Their work also might help scientists understand how different cells in the body turn genes on and off to perform different functions.
“Every cell in your body will have the same DNA, but the cells in your eyeballs are very different from the cells in your skins, which are very different from the neurons in your brain,” said Adrian Sanborn, the other co-author of the study. “Folding of the genome is at the heart of the question of how do cells get all this information.”
— Markian Hawryluk, The Houston Chronicle