Supercomputers reveal how X chromosomes fold and turn off

Using dynamic modeling driven by a supercomputer and based on experimental data, researchers can now probe the process that deactivates an X chromosome in female mammalian embryos. This new ability helps biologists understand the role of RNA and chromosome structure in the X inactivation process, leading to a better understanding of gene expression and opening new avenues for treatments. medicinal for genetic disorders and diseases.

“This is the first time that we have been able to model all the RNA that is spreading around the chromosome and stop it,” said Anna Lappala, visiting scientist at Los Alamos National Laboratory and polymer physicist in Massachusetts. General Hospital and the Harvard Department. of molecular biology. Lappala is the first author of the article published on October 4 in the Proceedings of the National Academy of Sciences. “From the experimental data alone, which is 2D and static, you don’t have the resolution to see an entire chromosome at this level of detail. With this modeling, we can see the processes regulating gene expression, and the modeling is based on 2D. experimental data from our collaborators at Massachusetts General Hospital and Harvard. “

The model, considered 4D because it shows movement, including time as a fourth dimension, runs on Los Alamos supercomputers. The model also incorporates experimental data from mouse genomes obtained using a molecular method called 4DHiC. The combined molecular and computational methodology is a first.

In the visualization, RNA particles swarm on the X chromosome. The tangled spaghetti-like strands twist, change shape, and then the particles rush and penetrate the depths of the chromosome, deactivating it. See the visualization:

“The method allows us to develop an interactive model of this epigenetic process,” said Jeannie T. Lee, professor of genetics at Harvard Medical School and vice president of molecular biology at Massachusetts General Hospital, whose lab provided the data. experiments that underlie the model.

Epigenetics is the study of changes in gene expression and hereditary traits that do not involve mutations in the genome.

“What is missing in the field is a way for a user who is not math-savvy to interactively enter a chromosome,” Lee said. She compared using the Los Alamos model to using Google Earth, where “you can zoom anywhere on an X chromosome, pick your favorite gene, see the other genes around it, and see how they go. interact “. This ability could provide insight into how diseases are spread, for example, she said.

Based on the work in this article, Los Alamos is currently developing a Google Earth-style browser where any scientist can download their genomic data and dynamically visualize it in 3D at various magnifications, said Karissa Sanbonmatsu, structural biologist at Los Alamos National Laboratory. , corresponding author of the article and project leader in the development of the calculation method.

In mammals, a female embryo is conceived with two X chromosomes, one inherited from each parent. Inactivation of X shuts down the chromosome, a crucial step for the survival of the embryo, and variations in X inactivation can trigger a variety of developmental disorders.

Los Alamos’ new model will facilitate a deeper understanding of gene expression and related issues, which could lead to pharmacological treatments for various diseases and genetic disorders, Lee said.

“Our main goal was to see the chromosome change shape and see the levels of gene expression over time,” said Sanbonmatsu.

To understand how genes are turned on and off, said Sanbonmatsu, “it is really helpful to know the structure of the chromosome. The hypothesis is that a tightly-structured and compacted chromosome tends to turn genes off, but there is no isn’t a lot of smoking guns. about it. By modeling moving 3D structures, we can get closer to the relationship between structural compaction and gene deactivation. “

Lee compared the structure of the chromosome to origami. A complicated shape similar to an origami crane provides a lot of surface area for gene expression and might be biologically preferred for staying active.

The model shows a variety of substructures in the chromosome. When closed, “it’s a piecemeal process in which some substructures are kept but some are dissolved,” Sanbonmatsu said. “We see early, middle and final stages, through a gradual transition. This is important for epigenetics because this is the first time that we have been able to analyze the detailed structural transition in an epigenetic change.”

The modeling also shows genes on the surface of the chromosome that escape the inactivation of the X chromosome, confirming the first experimental work. In the model, they cluster together and apparently interact or work together on the surface of the chromosome.

In another look at modeling, “As the chromosome changes from an active X, when it is still large enough, to a compact inactive X, i.e. smaller, we notice that there is a nucleus of the chromosome that is extremely dense, but the surface is much less dense. We’re also seeing a lot more movement on the surface, ”Lappala said. “Then there is an intermediate region that is neither too fast nor too slow, where the chromosome can rearrange.”

An inactive X can activate later in a process called age-related activation of the inactive X. “It’s associated with problems in blood cells in particular that are known to cause autoimmunity,” Lee said. “Some research attempts to pharmacologically activate inactive X to treat neurological disorders in children by giving them back something that is missing on their active X chromosome. For example, a child might have a mutation that can cause disease. We believe that if we can reactivate the normal copy on the inactive X, then we would have epigenetic treatment for this mutation. ”