Supercomputer reveals how the X chromosome folds and deactivates

RNA particles cluster the X chromosome from mice in a new visualization of X-chromosome inactivation.Credit: Los Alamos National Laboratory

Using supercomputer-driven dynamic modeling based on experimental data, researchers can now scrutinize the process of turning off one X chromosome in a female mammalian embryo. This new function helps biologists understand the role of RNA in the X-chromosome inactivation process and the structure of chromosomes, leading to a deeper understanding of gene expression and new approaches to drug treatment of gene-based disorders and disorders. Open the way.

“This is the first time we have been able to model and shut down all the RNA that spreads around the chromosome,” said Anna Lapara, a visiting scientist at the Los Alamos National Laboratory and a polymer physicist at Massachusetts General Hospital and Harvard University. Says. Of molecular biology. Lappala is the first author of a paper published on October 4th. Minutes of the National Academy of Sciences.. “2D static experimental data alone does not have the resolution to see the entire chromosome at this level of detail. Using this modeling, we can see that we are controlling the process. Gene expressionThe modeling is based on 2D experimental data from collaborators at Massachusetts General Hospital and Harvard. “

This model is considered 4D because it shows movements that include time as 4 dimensions and runs on a Los Alamos supercomputer. The model also incorporates experimental data from the mouse genome obtained by a molecular method called 4DHiC. The first is a methodology that combines molecules and calculations.

In the visualization, RNA particles are clustered on the X chromosome. Tangled spaghetti-like strands writhe and reshape, then particles swallow and penetrate the depth of the chromosomes, turning them off. See visualization:

“This method allows us to develop an interactive model of this epigenetic process,” said Genie T. Lee, a professor of genetics at Harvard Medical School and vice chairman of molecular biology at Massachusetts General Hospital. increase. Experimental data Supports the model.

Epigenetics is the study of gene expression and changes in genetic traits without genomic mutations.

“What’s lacking in this area is a way for non-computational users to enter the chromosome interactively,” Lee said. She compared the use of the Los Alamos model with the use of Google Earth. Here, “You can zoom in anywhere on the X chromosome, select your favorite gene, and see other genes. gene Look around it and see how they interact. “That ability can give insight into, for example, how the disease spreads, she said.

Based on the study in this paper, Los Alamos National Laboratory structural biologist Carissa Sanbonmatsu said that Los Alamos is now a Google Earth style that allows scientists to upload genomic data and dynamically view it in 3D at various magnifications. I am developing a browser for. Corresponding author of the treatise, and project leader in the development of computational methods.

In mammals, female embryos become pregnant with two Xs Chromosomes, Inherited from each parent. X-chromosome inactivation blocks the chromosome, which is an important step for embryo survival, and changes in X-chromosome inactivation can cause a variety of developmental disorders.

The new Los Alamos model facilitates a deeper understanding of the problems associated with gene expression, which could lead to pharmacological treatment of various gene-based diseases and disorders, Lee said.

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

To understand the on and off of genes, Sanbonmatsu said, “Knowing the structure of chromosomes is really helpful. The hypothesis is that compressed, well-structured chromosomes tend to turn off genes. But there aren’t many smoking guns. About this. By modeling a moving 3D structure, we can get closer to the relationship between structural compression and gene off. “

Lee likened the structure of chromosomes to origami. Complex shapes that resemble paper cranes provide many surfaces for gene expression and may be preferred to maintain biological activity.

This model shows various substructures of chromosomes. When closed, “a fragmentary process in which some substructures are maintained and some are dissolved,” said Sanbonmatsu. “Through a gradual transition, we see beginning, intermediate, and ending stages. It’s important for epigenetics because it’s the first time we’ve been able to analyze detailed structural transitions in epigenetic changes.”

Modeling also shows genes on the surface of the chromosome that avoid X-chromosome inactivation, confirming early experimental work. In the model, they cluster and clearly interact or work together on the surface of the chromosome.

Another insight from modeling is that “when you move from an active X when the chromosome is still quite large to a small, compact, inactive X, you find that the core of the chromosome is very dense, but the surface is It’s much smaller. It’s denser. There’s more movement on the surface. ” “Next, there is an intermediate region where the chromosomes can be rearranged, not too fast or too slow.”

Inactive X can be activated later in a process called age-related activation of the inactive X. “This is especially related to blood cell problems that are known to cause autoimmunity,” said Lee. “Some studies are trying to treat a child’s neuropathy by activating the Inactive X and returning what is missing the active X chromosome to the child. For example, the child causes the disease. You may have a possible mutation. We are wondering if it can be reactivated. If it is a normal copy of the inactive X, we will receive epigenetic treatment for that mutation. Become.”

Research reveals new clues about the structure of the X chromosome

For more information:
4D chromosome remodeling reveals the spatiotemporal rearrangement of the mammalian X chromosome. PNAS (2021).

Quote: Supercomputer reveals how the X chromosome is folded and deactivated (October 4, 2021).

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Supercomputer reveals how the X chromosome folds and deactivates

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