In collaboration with Oxford Nanopore Technologies, Weill Cornell Medicine and New York Genome Center researchers have developed a new method to assess the genome's three-dimensional structure on a large scale. It is an organism's genome, made up of all the genetic instructions, DNA or RNA, that allows it to function.

Scientists have found that cell function, including gene expression, may be influenced by groups of simultaneously interacting regulatory elements in the genome rather than by pairs of these elements. Their findings, published in Nature Biotechnology on May 30, may shed light on the relationship between genome structure and cellular identity.

Researchers will be better able to understand how the genome functions and particularly how it encodes different cell identities with the help of three-dimensional genome structure, said the study's senior author, Dr. Marcin Imieli*ski, associate professor at Weill Cornell Medicine and the New York Genome Center and member of its advisory board.

'We have gained amazing insights from studying genome structure, but there are key limitations as well,' he said.

Researchers have been able to look at how frequently two genetic loci interact with one another using previous technology to assess the three-dimensional structure of the genome.

In the past, scientists have observed pairs of loci called enhancers and promoters as components in the genome that interact to influence gene expression.

These pairings provide incomplete insight into the structure and function of the genome. A folding pattern, for instance, can be related to how the genome encodes a specific cell type, such as a liver, lung, or epithelial cell, said Dr. Imieliński, who is also a member of the Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Theoretically, this folding influences gene expression. 'How cell types are encoded in DNA, especially its structure, has remained a mystery.

A recent graduate of the Tri-Institutional Ph.D. Program in Computational Biology & Medicine, Aditya Deshpande, worked in Dr. Imieli*ski's lab and developed a new genome-wide assay so they can study groups of loci, not just pairs.

Hi-C (chromatin conformation capture), which measures a mixture of DNA and proteins to assess three-dimensional genome structure, was adapted to nanopore sequencing, which is the high-throughput sequencing of long, continuous DNA molecules.

Pore-C, the assay that resulted, enabled the researchers to observe tens of millions of three-dimensional locus groupings.

Statistical methods were also developed to determine which locus groupings were important and whether they interacted cooperatively to affect gene expression.

According to Dr. Imieli*ski, many three-dimensional interactions of the genome have no importance. As a key finding of the study, the researchers found that cooperative groupings of DNA elements occurred around genes linked to cell identity.

In the future, experiments will be conducted to determine which specific groupings of genomic components have an impact on cell identity. Researchers may also be able to use the new technology to understand how stem cells, immature, master cells of the body, differentiate into different cell types.

In addition, researchers may be able to better understand cancer cells. Ultimately, Dr. Imieli*ski believes that this technology will help us to understand how cancer cells restructure their genomes, and how those rearrangements can alter the identities of cells, thereby allowing cancer to spread.