†Nanowork NewsResearchers from Weill Cornell Medicine and the New York Genome Center, in collaboration with Oxford Nanopore Technologies, have developed a new method for large-scale assessment of the three-dimensional structure of the human genome, i.e. how the genome folds. The genome is the complete set of genetic instructions, DNA or RNA, that enable an organism to function.
Using this method, the researchers demonstrated that cell function, including gene expression, can be influenced by groups of cooperating regulatory elements in the genome rather than pairs of these components. Their findings, published in Nature Biotechnology †“Team Architecture in 3D Genomic Interactions Revealed by Nanopore Sequencing”), may help shed light on the relationship between genome structure and cellular identity.
“Knowing the three-dimensional genome structure will help researchers better understand how the genome functions, and in particular how it codes for different cell identities,” said senior author Dr. Marcin Imieliński, associate professor of pathology and laboratory medicine and computational genomics in computational biomedicine at Weill Cornell Medicine and a core member of the New York Genome Center. “The ways in which we have had to study genome structure have given us some amazing insights, but there were also important limitations,” he said.
For example, with previous technology to assess the three-dimensional structure of the genome, researchers have been able to study how often two loci, or physical locations on the genome, interact with each other. Traditionally, pairs of loci called enhancers and promoters – components in the genome that interact with each other to affect gene expression – have been observed.
Information about these links provides incomplete insight into the structure and function of the genome. For example, linking a folding pattern to how the genome codes for a specific cell identity — such as a liver, lung or epithelial cell — has been difficult, said Imieliński, who is also a member of the Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Society. Center at Weill Cornell Medicine. Scientists have theorized that this folding affects gene expression. “But how cell types are encoded, particularly in the structure of DNA, has been a mystery,” he said.
Imieliński and his research team, including first author Aditya Deshpande, a recent graduate of the Tri-Institutional Ph.D. Program in Computational Biology & Medicine, working in Imieliński’s lab, developed a new genome-wide test and algorithm that allows them to study groups of loci, not just pairs.
They adapted a traditional technology, Hi-C (chromatin conformation capture), which assesses a mixture of DNA and protein to analyze the three-dimensional genome structure, to nanopore sequencing or the high-throughput sequencing of long, continuous strands of DNA molecules. . The resulting test, which the researchers dubbed Pore-C, allowed them to observe tens of millions of three-dimensional locus alignments.
They also developed statistical methods to determine which locus groupings were important, based on whether they interacted cooperatively to influence gene expression. “Many three-dimensional interactions of the genome are not important,” Imieliński said. “Our analytical methods help us prioritize the group interactions likely to be important for genome function.” As a key finding of the study, the researchers found that the most significant cooperative groupings of DNA elements occurred around genes related to cell identity.
Future experiments will investigate which specific groupings of genomic components are essential for different aspects of cell identity. The new technology may also help researchers understand how stem cells, the body’s main immature cells, differentiate into different cell types.
In addition, researchers may be able to better understand abnormalities in cancer cells. “In the future, this technology could be very useful for understanding how the genome of cancer cells is rearranged and how those rearrangements drive the altered cell identities that allow cancers to grow and spread,” Imieliński said.
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