An interdisciplinary team from the Centre for Genomic Regulation (CRG) and the Institute for Research in Biomedicine (IRB Barcelona) has developed an imaging technique that captures the structure of the human genome to reveal how individual genes fold at the nucleosome level — the fundamental units constituting the genome’s three-dimensional architecture. The technique integrates superresolution imaging with advanced computational modeling. According to the researchers, the method allowed them to image the structure of the human genome at unprecedented resolution. They believe the technique could have a long-term impact on scientific discovery. Scientists used the technology, called Modeling immuno-OligoSTORM (MiOS), to create and virtually navigate 3D models of genes. Since almost every human disease has some basis in genes, the ability to visualize how genes work could lead scientists to a better understanding of how genes affect the health of the human body. The developers of MiOS hypothesized that taking superresolution microscopy and merging it with advanced computational tools could be a way to image genes at the level of detail necessary to study their shape and function, so as to fully understand their function and regulation. MiOS showed the distribution of nucleosomes within specific genes in superresolution, through the simultaneous visualization of DNA and histones. It integrated this information with restraint-based and coarse-grained modeling approaches. It allowed quantitative modeling of genes with nucleosome resolution and provides information about chromatin accessibility for regulatory factors such as RNA polymerase II. Comparison of a MiOS-obtained image to that obtained with a conventional microscope. (Left) A conventional microscope is used to visualize the structure of NANOG gene, which shows up as a bright green spot. (Right) The image of the gene taken through MiOS, which can image individual genes. The MiOS image has roughly 10 times better resolution and also details critical aspects of the structure that are not discernible using conventional methods. Courtesy of Vicky Neguembor/CRG and Pablo Dans/IRB Barcelona. The researchers used MiOS to explore intercellular variability, transcriptional-dependent gene conformation, and folding of housekeeping and pluripotency-related genes in human pluripotent and differentiated cells. MiOS demonstrated a high degree of resolution and data integration, revealing structures and details in genes that are not captured using conventional techniques. According to researcher Juan Pablo Arcon, the method provided a picture, or movie, of the 3D shape of genes at resolutions beyond the size of nucleosomes, reaching the scales that are needed to understand in detail the interaction between chromatin and other cell factors. “We show that MiOS provides unprecedented detail by helping researchers virtually navigate inside genes, revealing how they are organized at a completely new scale,” researcher Vicky Neguembor said. “It is like upgrading from the Hubble Space Telescope to the James Webb, but instead of seeing distant stars we’ll be exploring the farthest reaches inside a human nucleus.” In the future, observations on genetic information obtained through MiOS could be used to catalog variations in the shape of genes that cause disease, for example. MiOS could also be used to test drugs that may be able to treat a disease by changing the shape of an aberrant gene. The researchers intend to develop MiOS further, adding additional functionality that can, for example, detect how transcription factors (i.e., proteins involved in the process of transcribing DNA into RNA) bind to DNA. The research was published in Nature: Structural & Molecular Biology (www.doi.org/10.1038/s41594-022-00839-y).