Purple Genome DNA

Unprecedented detail: researchers capture how genes fold and function

purple genome dna

This technique is the most complete to date for studying the shape of genes.

The new technique is “like upgrading the Hubble to the James Webb”.

A new imaging technique captures the three-dimensional architecture of the human genome in unprecedented detail, showing how individual genes fold at the level of nucleosomes, the fundamental units that make up the three-dimensional architecture of the genome.

The technology, which was created by Barcelona researchers from the Center for Genomic Regulation (CRG) and the Institute for Research in Biomedicine (IRB Barcelona), combines high-resolution microscopy with sophisticated computer modelling. This is the most complete technique to date for studying the shape of genes.

The new technique allows researchers to digitally create and navigate three-dimensional models of genes, seeing not only their architecture, but also information about their movement or flexibility. Understanding how genes work could help us better understand how they influence the human body on both health and disease since almost all human diseases have a genetic basis.

Before and after using MiOS to image the genome

Comparison using a conventional microscope (left) to visualize the structure of the NANOG gene, which appears as a bright green spot compared to using MiOS (right) which can image individual genes. MiOS has about ten times better resolution and also details critical aspects of the structure that are not discernible with conventional methods. Credit: Vicky Neguembor/CRG and Pablo Dans/IRB Barcelona

Scientists will eventually be able to use this knowledge to predict what happens to genes when things go wrong, for example by cataloging differences in the structure of genes that cause disease. The method could potentially be used to test drugs that alter the shape of an aberrant gene, helping to develop new treatments for various diseases.

The technology is the next evolution of imaging techniques used to study living organisms, which began over four hundred years ago with the creation of microscopes. These have played a crucial role in the advancement of medicine and human health, for example, used by Robert Hooke to describe cells for the first time and later used by Santiago Ramón y Cajal to identify neurons. Despite great advances, the limitations of optical microscopes were clear as early as 1873, with researchers stipulating that their maximum resolution could not exceed 0.2 micrometers.

This physical limit was surpassed in the 21st century with the creation of super-resolution microscopy, a breakthrough that received the Nobel Prize in Chemistry in 2014. Using fluorescence, researchers have pushed the boundaries of optical microscopy and captured events at 20 nanometers, a feat that revealed how life works on an unprecedented molecular scale.

MiOS captures genes in unprecedented detail

Example of a MiOS model showing how a gene folds in 3D. This reveals how some regions are compacted and others stretched and more accessible. Credit: Pablo Dans/IRB Barcelona

Super-resolution microscopy has changed the course of biomedical research, allowing scientists to track proteins in a variety of diseases. It has also allowed researchers to study the molecular events that regulate gene expression. Scientists now want to build on the technology and go further by adding more layers of information.

The researchers hypothesized that super-resolution microscopy and its fusion with advanced computational tools could be a way to image genes at the level of detail needed to study their form and function. An interdisciplinary team of scientists shared their expertise and created a new technique called Immuno-OligoSTORM Modeling – or MiOS for short.

The two research groups have partnered under the Ignite call of the Barcelona Institute of Science and Technology (BIST), which facilitates the exchange of knowledge between different scientific fields and explores new approaches to solving questions. complex.

MiOS Team

From left to right: Pia Cosma, Laura Martin, Rafael Lema, Ximena Garate, Victoria Neguembor, Pablo Dans, Juan Pablo Arcon, Jürgen Walther, Isabelle Brun Heath, Pablo Romero, Diana Buitrago. Credit: BIST

“Our computer modeling strategy incorporates data

DNA, or deoxyribonucleic acid, is a molecule made up of two long strands of nucleotides that wrap around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth and reproduction. Almost all cells in a person’s body have the same DNA. Most DNA is found in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).

” data-gt-translate-attributes=”[{” attribute=””>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,” says Dr. Juan Pablo Arcon, co-first author of the work and postdoctoral researcher at IRB Barcelona.

As proof of concept, the research team used MiOS to provide new insights on the position, shape, and compaction of key housekeeping and pluripotency genes, revealing new structures and details that are not captured using conventional techniques alone. The findings are published in the journal Nature Structural & Molecular Biology. The study’s corresponding authors include ICREA Research Professor Pia Cosma at the CRG and Professor Modesto Orozco at IRB Barcelona, as well as Pablo Dans, previously a researcher at IRB Barcelona and now at University of the Republic (Uruguay) and the Institut Pasteur of Montevideo.

“We show that MiOS provides unprecedented detail by helping researchers virtually navigate inside genes, revealing how they are organized at a completely new scale. It is like upgrading from the
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