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Super-resolution microscopy technique visualises gene folding in unprecedented detail

In a recent paper, published in Nature, researchers have revealed a new super-resolution microscopy technique that allows the genome to be imaged at the nucleosome level. The technique enables scientists to gain a better understanding of gene function and shape, and could aid the discovery of new treatments for a range of diseases.

Manipulating microscopy

The DNA sequence of a gene can only tell you so much about how it functions. To fully understand the complexities of gene regulation and function, we need to delve deeper into how it folds in the 3-dimensional nuclear space. To aid in this quest, researchers from the Center for Genomic Regulation and the Institute for Research in Biomedicine (based in Barcelona, Spain) turned to microscopy.

Though it has been around a while, microscopy was largely overlooked for a long time by the research community. However, in the 21st century, several breakthroughs led to the development of super-resolution microscopy, allowing scientists to capture cellular events down to 20 nanometres. This changed the course of biomedical research, and the field of proteomics blossomed. However, more information was still required to fully understand gene shape and function in the context of disease.

To overcome this challenge, the Barcelona-based team combined super-resolution microscopy with powerful computational tools. The resulting new technique, called Modeling immune-OligoSTORM (MiOS) allowed them to view the distribution of nucleosomes within specific genes in super-resolution through the simultaneous visualisation of DNA and histones. Combined with modelling, it can provide information about chromatin accessibility for regulatory factors such as RNA polymerase II.

This is the most comprehensive method to date for studying the shape of genes, allowing researchers to virtually navigate 3D models of genes to comprehend intimate details about how they move and how flexible they are.

Gene folding at the nucleosome scale

Importantly, the information gathered can be used to predict what happens to genes when things go wrong – for example, cataloguing the variations in the shape of genes that cause disease or testing potential drug candidates that change the shape of an aberrant gene.

“Our computational modelling strategy integrates data from DNA sequencing techniques and super-resolution microscopy to provide an essential picture (or movie) of the 3D shape of genes at resolutions beyond the size of nucleosomes, reaching the scales needed to understand in detail the interaction between chromatin and other cell factors,” said Dr. Juan Pablo Arcon, co-first author of the work and postdoctoral researcher at IRB Barcelona. 

The technique has yet to be applied to a specific research aim, but as a proof-of-concept, the team used MiOS to look at the position, shape and compaction of key housekeeping and pluripotency genes.

Figure 1: Before and after using MiOS to image genome. Comparison using a conventional microscope (left) to visualise the structure of NANOG gene, which shows up as a bright green spot vs. using MiOS (right) which can image individual genes. MiOS is roughly ten times better resolution and also details critical aspects of the structure that are not discernible using conventional methods. Credit: Vicky Neguembor/CRG and Pablo Dans/IRB Barcelona.

“We show that MiOS provides unprecedented detail by helping researchers virtually navigate inside genes, revealing how they are organised at a completely new scale,” said Dr. Vicky Neguembor, co-first author of the study and researcher at the CRG. “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.” 

The applications of MiOS are exciting, but a lot of work still needs to be done to validate the technique before the potential payoffs can be realised. Still, the team have already begun working on using MiOS to explore human development genes and hope to add additional functionality that could allow scientists to explore how transcription factors bind to DNA. The long-term goal is that the extensive detail and information provided by MiOS will aid the translation of new discoveries into clinical practice.