(News from Nanowerk) Researchers from Weill Cornell Medicine and the New York Genome Center, in collaboration with Oxford Nanopore Technologies, have developed a new method to assess on a large scale the three-dimensional structure of the human genome, or how the genome folds. The genome is the complete set of genetic instructions, DNA or RNA, allowing an organism to function.
Using this method, the researchers demonstrated that cellular function, including gene expression, can be affected by groups of simultaneously interacting regulatory elements in the genome rather than by pairs of these components. Their findings, published in Natural biotechnology (“Team architecture in 3D genomic interactions revealed by nanopore sequencing”), may help shed light on the relationship between genome structure and cell identity.
“Knowing the three-dimensional structure of the genome will help researchers better understand how the genome works, and in particular how it encodes different cell identities,” said lead author Dr. Marcin Imieliński, associate professor of pathology and laboratory medicine. and Computational Genomics in Computational Biomedicine at Weill Cornell Medicine and Senior Fellow of the New York Genome Center. “The ways we had to study the structure of the genome gave us incredible insights, but there were also significant limitations,” he said.
For example, previous technology for assessing the three-dimensional structure of the genome has allowed researchers 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 of the genome that interact with each other to influence gene expression – have been observed.
Information about these pairings offers incomplete insight into genome structure and function. 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 fellow at the England Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. Scientists have hypothesized that this folding influences gene expression. “But how cell types are coded, especially in DNA structure, is a mystery,” he said.
Imieliński and his research team, including first author Aditya Deshpande, a recent graduate of the tri-institutional doctorate. The Computational Biology and Medicine program working in Imieliński’s lab has 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 proteins to analyze the three-dimensional structure of the genome, to nanopore sequencing or high-throughput sequencing of long continuous strands of DNA molecules. The resulting assay, which the researchers called Pore-C, allowed them to observe tens of millions of three-dimensional locus clusters.
They also developed statistical methods to determine which clusters of loci were important based on whether they interacted cooperatively to affect gene expression. “Many three-dimensional interactions in the genome are not important,” Imieliński said. “Our analytical methods help us prioritize group interactions that may impact genome function.” As the main finding of the study, the researchers found that the most important cooperative groupings of DNA elements occur around genes associated with cellular identity.
Future experiments will explore which specific groupings of genomic components are essential for various aspects of cell identity. The new technology may also help researchers understand how stem cells, the body’s immature master cells, differentiate into different cell types.
In addition, researchers could better understand the abnormalities of cancer cells. “In the future, this technology could be very useful in understanding how cancer cell genomes are rearranged and how these rearrangements result in the altered cell identities that allow cancers to grow and spread,” Imieliński said.
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